Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation

ABSTRACT

A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula II:                    
     wherein R 2  is selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl; wherein R 3  is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo; and wherein R 4  is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R 4  is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocyclic and amino; provided R 2  and R 3  are not both hydrido; further provided that R 2  is not carboxyl or methyl when R 3  is hydrido and when R 4  is phenyl; further provided that R 4  is not triazolyl when R 2  is methyl; further provided that R 4  is not aralkenyl when R 2  is carboxyl, aminocarbonyl or ethoxycarbonyl; further provided that R 4  is not phenyl when R 2  is methyl and R 3  is carboxyl; and further provided that R 4  is not unsubstituted thienyl when R 2  is trifluoromethyl; or a pharmaceutically-acceptable salt thereof.

This is a continuation of application Ser. No. 10/125,325 filed Apr. 17,2002, now U.S. Pat. No. 6,492,411 which is a continuation of Ser. No.09/609,011 filed May 30, 2000, now U.S. Pat. No. 6,413,960 which is acontinuation of Ser. No. 09/449,076, filed Nov. 24, 1999, now U.S. Pat.No. 6,156,781 which is a continuation of Ser. No. 08/957,345, filed Oct.24, 1997, now abandoned, which is a continuation of Ser. No. 08/648,113,filed Sep. 6, 1996, now issued as U.S. Pat. No. 5,760,068, which is acontinuation of PCT/US94/12720, filed Nov. 11, 1994, which is acontinuation of Ser. No. 08/223,629, filed Apr. 6, 1994, now issued asU.S. Pat. No. 5,521,207, which is a continuation-in-part of Ser. No.08/160,594, filed Nov. 30, 1993, now issued as U.S. Pat. No. 5,466,823.

FIELD OF THE INVENTION

This invention is in the field of anti-inflammatory pharmaceuticalagents and specifically relates to compounds, compositions and methodsfor treating inflammation and inflammation-associated disorders, such asarthritis.

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process and theinhibition of prostaglandin production, especially production of PGG₂,PGH₂ and PGE₂, has been a common target of anti-inflammatory drugdiscovery. However, common non-steroidal anti-inflammatory drugs(NSAIDs) that are active in reducing the prostaglandin-induced pain andswelling associated with the inflammation process are also active inaffecting other prostaglandin-regulated processes not associated withthe inflammation process. Thus, use of high doses of most common NSAIDscan produce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).The recent discovery of an inducible enzyme associated with inflammation(named “cyclooxygenase II (COX II)” or “prostaglandin G/H synthase II”)provides a viable target of inhibition which more effectively reducesinflammation and produces fewer and less drastic side effects.

Pyrazoles have been described for use in the treatment of inflammation.U.S. Pat. No. 5,134,142 to Matsuo et al describes 1,5-diaryl pyrazoles,and specifically,1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-trifluoromethylpyrazol, as having anti-inflammatory activity.

U.S. Pat. No. 3,940,418 to R. Hamilton describes tricyclic4,5-dihydrobenz[g]indazoles as antiinflammatory agents. In addition, R.Hamilton [J. Heterocyclic Chem., 13, 545 (1976)] describes tricyclic4.5-dihydrobenz[g]indazoles as antiinflammatory agents. U.S. Pat. No.5,134,155 describes fused tricyclic pyrazoles having a saturated ringbridging the pyrazole and a phenyl radical as HMG-CoA reductaseinhibitors. European publication EP 477,049, published Mar. 25, 1992,describes [4,5-dihydro-1-phenyl-1H-benz[g]indazol-3-yl]amides as havingantipsychotic activity. European publication EP 347,773, published Dec.27, 1989, describes[4,5-dihydro-1-phenyl-1H-benz[g]indazol-3-yl]propanamides asimmunostimulants. M. Hashem et al [J. Med. Chem., 19, 229 (1976)]describes fused tricyclic pyrazoles, having a saturated ring bridgingthe pyrazole and a phenyl radical, as antibiotics.

Certain substituted pyrazolyl-benzenesulfonamides have been described inthe literature as synthetic intermediates. Specifically,4-[5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl]benzenesulfonamide hasbeen prepared from a pyrazoline compound as an intermediate forcompounds having hypoglycemic activity [R. Soliman et al, J. Pharm.Sci., 76, 626 (1987)].4-[5-[2-(4-Bromophenyl)-2H-1,2,3-triazol-4-yl]-3-methyl-1H-pyrazol-1-yl]benzenesulfonamidehas been prepared from a pyrazoline compound and described aspotentially having hypoglycemic activity [H. Mokhtar, Pak. J. Sci. Ind.Res., 31, 762 (1988)]. Similarly,4-[4-bromo-5-[2-(4-chlorophenyl)-2H-1,2,3-triazol-4-yl]-3-methyl-1H-pyrazol-1-yl]benzenesulfonamidehas been prepared [H. Mokhtar et al, Pak. J. Sci. Ind. Res., 34, 9(1991)].

The phytotoxicity of pyrazole derivatives is described [M. Cocco et al,Il. Farmaco-Ed. Sci., 40, 272 (1985)], specifically for1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3,4-dicarboxylic acid.

The use of styryl pyrazole esters for antidiabetes drugs is described[H. Mokhtar et al, Pharmazie, 33, 649-651 (1978)]. The use of styrylpyrazole carboxylic acids for antidiabetes drugs is described [R.Soliman et al, Pharmazie, 33, 184-5 (1978)]. The use of4-[3,4,5-trisubstituted-pyrazol-1-yl]benzenesulfonamides asintermediates for sulfonylurea anti-diabetes agents is described, andspecifically,1-[4-(aminosulfonyl)phenyl]-3-methyl-5-phenyl-1H-pyrazole-4-carboxylicacid [R. Soliman et al, J. Pharm. Sci., 72, 1004 (1983)]. A series of4-[3-substituted methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamides hasbeen prepared as intermediates for anti-diabetes agents, and morespecifically, 4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide[H. Feid-Allah, Pharmazie, 36, 754 (1981)]. In addition,1-(4-[aminosulfonyl]phenyl)-5-phenylpyrazole-3-carboxylic acid has beenprepared from the above described4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide compound [R.Soliman et al, J. Pharm. Sci., 70, 602 (1981)].

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating inflammation-related disordersis defined by Formula (I):

wherein R¹ is selected from aryl and heteroaryl, wherein R¹ issubstituted at a substitutable position with one or more radicalsselected from sulfamyl, halo, alkyl, alkoxy, hydroxyl, haloalkyl and

wherein R² is selected from hydrido, halo, alkyl, haloalkyl, cyano,nitro, formyl, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, cyanoalkyl,alkoxycarbonylcyanoalkenyl, aminocarbonylalkyl, N-alkylaminocarbonyl,N-arylaminocarbonyl, N,N-dialkylaminocarbonyl,N-alkyl-N-arylaminocarbonyl, cycloalkylaminocarbonyl,heterocyclicaminocarbonyl, carboxyalkylaminocarbonyl,aralkoxycarbonylalkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkyl,hydroxyalkyl, haloaralkyl, carboxyhaloalkyl, alkoxycarbonylhaloalkyl,aminocarbonylhaloalkyl, alkylaminocarbonylhaloalkyl, N-alkylamino,N,N-dialkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,N-alkyl-N-arylamino, aminoalkyl, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,aralkoxy, arylthio, aralkylthio, alkylthio, alkylsulfinyl,alkylsulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl,N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, heterocyclic,

wherein R³ is selected from hydrido, alkyl, halo, haloalkyl, cyano,nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, amidino, cyanoamidino, aminocarbonyl, alkoxy,N-alkylamino, N,N-dialkylamino, aminocarbonylalkyl,N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl,N-alkyl-N-arylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkyl,hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl,N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, cycloalkyl,heterocyclic, heterocyclicalkyl and aralkyl;

wherein R⁴ is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyland heterocyclic; wherein R⁴ is optionally substituted at asubstitutable position with one or more radicals selected from halo,alkylthio, alkylsulfinyl, alkyl, alkenyl, alkylsulfonyl, cyano,carboxyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl,N-arylaminocarbonyl, N,N-dialkylaminocarbonyl,N-alkyl-N-arylaminocarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl,haloalkoxy, sulfamyl, N-alkylaminosulfonyl, amino, N-alkylamino,N,N-dialkylamino, heterocyclic, cycloalkylalkyl, nitro, acylamino,

 or wherein R³ and R⁴ together form

wherein m is 1 to 3, inclusive;

wherein A is selected from phenyl and five or six membered heteroaryl;

wherein R⁵ is alkyl;

wherein R⁶ is one or more radicals selected from halo, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl,aminocarbonyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, alkyl,alkenyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,haloalkyl, hydrido, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy,sulfamyl, N-alkylaminosulfonyl, amino, N-alkylamino, N,N-dialkylamino,heterocyclic, cycloalkylalkyl, nitro and acylamino; and

wherein R⁷ is selected from hydrido, alkyl, aryl and aralkyl;

provided R² and R³ are not identical radicals selected from hydrido,carboxyl and ethoxycarbonyl; further provided that R² is not carboxyl ormethyl when R³ is hydrido and when R⁴ is phenyl; further provided thatR⁴ is not triazolyl when R² is methyl; further provided that R⁴ is notaralkenyl when R² is carboxyl, aminocarbonyl or ethoxycarbonyl; furtherprovided that R⁴ is not phenyl when R² is methyl and R³ is carboxyl;further provided that R⁴ is not unsubstituted thienyl when R² istrifluoromethyl; and further provided that R⁴ is aryl substituted withsulfamyl or R⁶ is sulfamyl, when R¹ is phenyl not substituted withsulfamyl;

or a pharmaceutically-acceptable salt thereof.

The phrase “further provided”, as used in the above description, isintended to mean that the denoted proviso is not to be consideredconjunctive with any of the other provisos.

Compounds of Formula I would be useful for, but not limited to, thetreatment of inflammation in a subject, and for treatment of otherinflammation-associated disorders, such as, as an analgesic in thetreatment of pain and headaches, or as an antipyretic for the treatmentof fever. For example, compounds of Formula I would be useful to treatarthritis, including but not limited to rheumatoid arthritis,spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis. Such compounds of Formula I wouldbe useful in the treatment of asthma, bronchitis, menstrual cramps,tendinitis, bursitis, and skin related conditions such as psoriasis,eczema, burns and dermatitis. Compounds of Formula I also would beuseful to treat gastrointestinal conditions such as inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome andulcerative colitis and for the prevention of colorectal cancer.Compounds of Formula I would be useful in treating inflammation in suchdiseases as vascular diseases, migraine headaches, periarteritis nodosa,thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumaticfever, type I diabetes, myasthenia gravis, sarcoidosis, nephroticsyndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity,conjunctivitis, swelling occurring after injury, myocardial ischemia,and the like. The compounds are useful as antiinflammatory agents, suchas for the treatment of arthritis, with the additional benefit of havingsignificantly less harmful side effects.

The present invention preferably includes compounds which selectivelyinhibit cyclooxygenase II over cyclooxygenase I. Preferably, thecompounds have a cyclooxygenase II IC₅₀ of less than about 0.2 μM, andalso have a selectivity ratio of cyclooxygenase II inhibition overcyclooxygenase I inhibition of at least 50, and more preferably of atleast 100. Even more preferably, the compounds have a cyclooxygenase IIC₅₀ of greater than about 1 μM, and more preferably of greater than 10μM. Such preferred selectivity may indicate an ability to reduce theincidence of common NSAID-induced side effects.

A preferred class of compounds consists of those compounds of Formula Iwherein R¹ is selected from aryl selected from phenyl, naphthyl andbiphenyl, and five- or six-membered heteroaryl, wherein R¹ issubstituted at a substitutable position with one or more radicalsselected from sulfamyl, halo, lower alkyl, lower alkoxy, hydroxyl, lowerhaloalkyl and

wherein R² is selected from hydrido, halo, lower alkyl, lower haloalkyl,cyano, nitro, formyl, carboxyl, lower alkoxycarbonyl, lowercarboxyalkyl, lower alkoxycarbonylalkyl, amidino, cyanoamidino, lowercyanoalkyl, lower alkoxycarbonylcyanoalkenyl, aminocarbonyl, loweralkoxy, lower aryloxy, lower aralkoxy, lower aminocarbonylalkyl, lowerN-alkylaminocarbonyl, N-arylaminocarbonyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lowercycloalkylaminocarbonyl, lower heterocyclicaminocarbonyl, lowercarboxyalkylaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl,lower haloaralkyl, lower carboxyhaloalkyl, loweralkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, loweralkylaminocarbonylhaloalkyl, lower alkylcarbonyl, loweralkylcarbonylalkyl, lower alkylamino, lower N,N-dialkylamino,N-arylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lowerN-alkyl-N-arylamino, lower aminoalkyl, lower M-alkylaminoalkyl, lowerN,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lowerN-aralkylaminoalkyl, lower N-alkyl-N-aralkylaminoalkyl, lowerN-alkyl-N-arylaminoalkyl, arylthio, lower aralkylthio, lowerhydroxyalkyl, lower alkylthio, lower alkylsulinyl, lower alkylsulfonyl,lower N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, lowerN,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl,heterocyclic,

wherein R³ is selected from hydrido, lower alkyl, halo, lower haloalkyl,cyano, nitro, formyl, carboxyl, lower alkoxycarbonyl, lowercarboxyalkyl, lower alkoxycarbonylalkyl, amidino, cyanoamidino,aminocarbonyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino,lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, lowerN-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lowerN-alkyl-N-arylaminocarbonyl, lower alkylcarbonyl, loweralkylcarbonylalkyl, lower hydroxyalkyl, lower alkylthio, loweralkylsulfinyl, lower alkylsulfonyl, lower N-alkylaminosulfonyl,N-arylaminosulfonyl, arylsulfonyl, lower N,N-dialkylaminosulfonyl, lowerN-alkyl-N-arylaminosulfonyl, lower cycloalkyl, heterocyclic, lowerheterocyclicalkyl and lower aralkyl;

wherein R⁴ is selected from lower aralkenyl, aryl, lower cycloalkyl,lower cycloalkenyl and five to ten membered heterocyclic; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, lower alkylthio, lower alkylsulfinyl, loweralkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, loweralkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl,N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lowerN-alkyl-N-arylaminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy,lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lowerN-alkylaminosulfonyl, amino, lower N-alkylamino, lower N,N-dialkylamino,five- or six-membered heterocyclic, lower cycloalkylalkyl, nitro,acylamino,

 or wherein R³ and R⁴ together form

wherein m is 1 to 3, inclusive;

wherein A is selected from phenyl and five or six membered heteroaryl;

wherein R⁵ is lower alkyl;

wherein R⁶ is one or more radicals selected from halo, lower alkylthio,lower alkylsulfinyl, lower alkylsulfonyl, cyano, carboxyl, loweralkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl,N-arylaminocarbonyl, lower alkyl, lower alkenyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lowerhaloalkyl, hydrido, hydroxyl, lower alkoxy, lower hydroxyalkyl, lowerhaloalkoxy, sulfamyl, lower N-alkylaminosulfonyl, amino, lowerN-alkylamino, lower N,N-dialkylamino, five- or six memberedheterocyclic, lower cycloalkylalkyl, nitro and acylamino; and

wherein R⁷ is selected from hydrido, lower alkyl, aryl and loweraralkyl;

or a pharmaceutically-acceptable salt thereof.

A more preferred class of compounds consists of those compounds ofFormula I wherein R¹ is phenyl, wherein R¹ is substituted at asubstitutable position with one or more radicals selected from sulfamyl,halo, lower alkyl, lower alkoxy, hydroxyl, lower haloalkyl and

wherein R² is selected from hydrido, lower alkyl, lower haloalkyl,cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lowercyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lowercarboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, loweraminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lowerN-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino,lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, loweraminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lowerN-arylaminoalkyl, lower N-aralkylaminoalkyl, lowerN-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, aryloxy,lower aralkoxy, lower alkoxy, lower alkylthio, arylthio, loweraralkylthio, aminocarbonyl, lower aminocarbonylalkyl, lowerN-alkylaminocarbonyl, N-arylaminocarbonyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lowercycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl, loweraralkoxycarbonylalkylaminocarbonyl, lower hydroxyalkyl,

wherein R³ is selected from hydrido, lower alkyl, halo, cyano, lowerhydroxyalkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lowerN-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, lowerN,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl and lowercycloalkyl;

wherein R⁴ is selected from lower aralkenyl, aryl, lower cycloalkyl,lower cycloalkenyl and five to ten membered heterocyclic; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, lower alkylthio, lower alkylsulfinyl, loweralkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, loweralkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy,lower hydroxyalkyl, lower haloalkoxy, sulfamyl, loweralkylaminosulfonyl, amino, lower N-alkylamino, lower N,N-dialkylamino,five or six membered heterocyclic, lower cycloalkylalkyl, nitro,

 or wherein R³ and R⁴ together form

wherein m is 2:

wherein A is selected from phenyl and five or six membered heteroaryl;

wherein R⁵ is lower alkyl;

wherein R⁶ is one or more radicals selected from halo, lower alkylthio,lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl,cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl,hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl,amino, lower N-alkylamino, lower N,N-dialkylamino, lower cycloalkylalkyland nitro; and

wherein R⁷ is selected from hydrido, lower alkyl, aryl and loweraralkyl;

or a pharmaceutically-acceptable salt thereof.

An even more preferred class of compounds consists of those compounds ofFormula I wherein R¹ is phenyl, wherein R¹ is substituted at asubstitutable position with one or more radicals selected from sulfamyl,halo, lower alkyl, lower alkoxy and

wherein R² is selected from hydrido, lower alkyl, lower haloalkyl,cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lowercyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lowercarboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, loweraminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lowerN-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino,lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, loweraminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lowerN-arylaminoalkyl, lower N-aralkylaminoalkyl, lowerN-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, loweralkoxy, aryloxy, lower aralkoxy, lower alkylthio, arylthio, loweraralkylthio, aminocarbonyl, lower aminocarbonylalkyl, lowerN-alkylaminocarbonyl, N-arylaminocarbonyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lowercycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl, lowerheterocyclicaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl,lower hydroxyalkyl,

wherein R³ is selected from hydrido, lower alkyl, halo, cyano, lowerhydroxyalkyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino,lower alkylthio, lower alkylsulfonyl and lower cycloalkyl;

wherein R⁴ is selected from lower aralkenyl, aryl, lower cycloalkyl,lower cycloalkenyl and five to ten membered heterocyclic; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, lower alkylthio, lower alkylsulfinyl, loweralkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, loweralkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy,lower hydroxyalkyl, lower haloalkoxy, sulfamyl, amino, lowerN-alkylamino, lower N,N-dialkylamino, five or six membered heterocyclic,lower cycloalkylalkyl, nitro,

 or wherein R³ and R⁴ together form

wherein m is 2;

wherein A is selected from phenyl and five membered heteroaryl;

wherein R⁵ is lower alkyl;

wherein R⁶ is one or more radicals selected from halo, lower alkyl,lower alkylsulfonyl, lower haloalkyl, lower alkoxy, sulfamyl, amino andnitro; and

wherein R⁷ is selected from hydrido, lower alkyl, aryl and loweraralkyl;

or a pharmaceutically-acceptable salt thereof.

Within Formula I there is a subclass of compounds which consists ofcompounds wherein R¹ is phenyl substituted at a substitutable positionwith one or more radicals selected from halo, lower alkyl, sulfamyl and

wherein R² is selected from hydrido, lower alkyl, lower haloalkyl,cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lowercyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lowercarboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, loweraminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lowerN-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino,lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, loweraminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lowerN-arylaminoalkyl, lower N-aralkylaminoalkyl, lowerN-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, loweralkoxy aryloxy, lower aralkoxy, lower alkylthio, arylthio, loweraralkylthio, aminocarbonyl, lower aminocarbonylalkyl, lowerN-alkylaminocarbonyl, N-arylaminocarbonyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lowercycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl, loweraralkoxycarbonylalkylaminocarbonyl, lower hydroxyalkyl,

wherein R³ is selected from hydrido, lower alkyl, halo, cyano, lowerhydroxyalkyl, lower alkoxy, lower alkylthio, lower N-alkylamino, lowerN,N-dialkylamino, lower alkylsulfonyl and lower cycloalkyl;

wherein R⁴ is selected from lower aralkenyl, aryl, lower cycloalkyl,lower cycloalkenyl and five to ten membered heterocyclic; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, lower alkylthio, lower alkylsulfinyl, loweralkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, loweralkoxycarbonyl, aminocarbonyl, lower-haloalkyl, hydroxyl, lower alkoxy,lower hydroxyalkyl, lower haloalkoxy, sulfamyl, loweralkylaminocarbonyl, amino, lower N-alkylamino, lower N,N-dialkylamino,five or six membered heterocyclic, lower cycloalkylalkyl, nitro,

wherein R⁵ is lower alkyl; and

wherein R⁷ is selected from hydrido, lower alkyl, aryl and loweraralkyl;

or a pharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula I wherein R¹ is phenyl, substituted at a substitutableposition with one or more radicals selected from fluoro, chloro, methyl,sulfamyl and

wherein R² is selected from hydrido, methyl, ethyl, isopropyl,tert-butyl, isobutyl, hexyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromechyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,trifluoroacetyl, cyanomethyl, ethoxycarbonylcyanoethenyl,1,1-difluoro-1-phenylmethyl, 1,1-difluoro-1-phenylethyl, difluoroacetyl,methoxycarbonyldifluoromethyl, difluoroacetamidyl,N,N-dimethyldifluoroacetamidyl, N-phenyldifluoroacetamidyl,N-ethylamino, N-methylamino, N,N-dimethylamino, N,N-diethylamino,N-phenylamino, N-benzylamino, N-phenylethylamino,N-methyl-N-benzylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino,aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl,N-phenylaminomethyl, N-benzylaminomethyl, N-methyl-N-benzylaminomethyl,N-methyl-N-phenylaminomethyl, methoxy, ethoxy, phenoxy, benzyloxy,methylthio, phenylthio, benzylthio, N-methylurea, N-methylthiourea,N-methylacetamidyl, urea, ureamethyl, thiourea, thioureamethyl,acetamidyl, N-phenylthioureamethyl, N-benzylthioureamethyl,N-methylthioureamethyl, N-phenylureamethyl, N-benzylureamethyl,N-methylureamethyl, N-phenylacetamidylmethyl, N-benzylacetamidylmethyl,N-methylacetamidylmethyl, aminocarbonyl, aminocarbonylmethyl,N-methylaminocarbonyl, N-ethylaminocarbonyl, N-isopropylaminocarbonyl,N-propylaminocarbonyl, N-butylaminocarbonyl, N-isobutylaminocarbonyl,N-tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-phenylaminocarbonyl,N,N-dimethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl,N-(3-fluorophenyl)aminocarbonyl, N-(4-methylphenyl)aminocarbonyl,N-(3-chlorophenyl)aminocarbonyl,N-methyl-N-(3-chlorophenyl)aminocarbonyl,N-(4-methoxyphenyl)aminocarbonyl, N-methyl-N-phenylaminocarbonyl,cyclopentylaminocarbonyl, cyclohexylaminocarbonyl,carboxymethylaminocarbonyl, benzyloxycarbonylmethylaminocarbonyl,hydroxypropyl, hydroxymethyl, and hydroxypropyl;

wherein R³ is selected from hydrido, methyl, ethyl, isopropyl,tert-butyl, isobutyl, hexyl, fluoro, chloro, bromo, cyano, methoxy,methylthio, methylsulfonyl, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-diethylamino, cyclopronyl, cyclopentyl,hydroxypropyl, hydroxymethyl, and hydroxyethyl; and

wherein R⁴ is selected from phenylethenyl, phenyl, naphthyl, biphenyl,cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl,3-cyclohexenyl, 4-cyclohexenyl, 1-cyclopentenyl, 4-cyclopentenyl,benzofuryl, 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydronaphthyl,benzothienyl, indenyl, indanyl, indolyl, dihydroindolyl, chromanyl,benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl,pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R⁴is optionally substituted at a substitutable position with one or moreradicals selected from fluoro, chloro, bromo, methylthio,methylsulfinyl, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl,hexyl, ethylenyl, propenyl, methylsulfonyl, cyano, carboxyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,pentoxycarbonyl, aminocarbonyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, bromodifluoromethyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy,methylenedioxy, ethoxy, propoxy, n-butoxy, sulfamyl,methylaminosulfonyl, hydroxypropyl, hydroxylsopropyl, hydroxymethyl,hydroxyethyl, trifluoromethoxy, amino, N-methylamino, N-ethylanino,N-ethyl-N-methylamino, N,N-dimethylamino, N,N-diethylamino, formylamino,methylcarbonylamino, trifluoroacetamino, piperadinyl, piperazinyl,morpholino, cyclohexylmethyl, cyclopropylmethyl, cyclopentylmethyl,nitro,

 and

wherein R⁷ is selected from hydrido, methyl, ethyl, phenyl and benzyl;

or a pharmaceutically-acceptable salt thereof.

Within formula I there is a second subclass of compounds of highinterest wherein R¹ is phenyl substituted at a substitutable positionwith sulfamyl; wherein R² is selected from lower haloalkyl, cyano,carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, aminocarbonyl, lowerN-alkylaminocarbonyl, N-arylaminocarbonyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lowercycloalkylaminocarbonyl and lower hydroxyalkyl; wherein R³ and R⁴together form

wherein m is 2; wherein A is selected from phenyl and five memberedheteroaryl; and wherein R⁶ is one or more radicals selected from halo,lower alkyl, lower alkylsulfonyl, lower haloalkyl, lower alkoxy, aminoand nitro; or a pharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula I wherein R² is selected from fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,trifluoroacetyl, aminocarbonyl, N-methylaminocarbonyl,N-ethylaminocarbonyl, N-isopropylaminocarbonyl, N-propylaminocarbonyl,N-butylaminocarbonyl, N-isobutylaminocarbonyl,N-tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-phenylaminocarbonyl,N,N-dimethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl,N-(3-fluorophenyl)aminocarbonyl, N-(4-methylphenyl)aminocarbonyl,N-(3-chlorophenyl)aminocarbonyl, N-(4-methoxyphenyl)aminocarbonyl,N-methyl-N-phenylaminocarbonyl, cyclohexylaminocarbonyl, hydroxypropyl,hydroxymethyl and hydroxyethyl; wherein A is selected from phenyl, furyland thienyl; and wherein R⁶ is one or more radicals selected fromfluoro, chloro, bromo, methylsulfonyl, methyl, ethyl, isopropyl,tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, methoxy,methylenedioxy, ethoxy, propoxy, n-butoxy, amino, and nitro; or apharmaceutically-acceptable salt thereof.

Within Formula I there is a third subclass of compounds of high interestwherein R¹ is selected from phenyl, naphthyl, biphenyl, and five- orsix-membered heteroaryl, wherein R¹ is substituted at a substitutableposition with one or more radicals selected from halo, lower alkyl,lower alkoxy, hydroxyl and lower haloalkyl; wherein R² is selected fromlower haloalkyl; wherein R³ is hydrido; and wherein R⁴ is arylsubstituted at a substitutable position with sulfamyl; or apharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula I wherein R¹ is selected from phenyl, naphthyl, benzofuryl,benzothienyl, indolyl, benzodioxolyl, benzodioxanyl, pyridyl, thienyl,thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R¹ is substituted at asubstitutable position with one or more radicals selected from fluoro,chloro, bromo, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichloropropyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,methyl, ethyl, propyl, hydroxyl, methoxy, ethoxy, propoxy and n-butoxy;wherein R² is selected from fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,difluoroethyl, dichlorofluoromethyl, difluoropropyl, dichloroethyl anddichloropropyl; wherein R³ is hydrido; and wherein R⁴ is phenylsubstituted at a substitutable position with sulfamyl; or apharmaceutically-acceptable salt thereof.

Within Formula I there is a subclass of compounds of high interestrepresented by Formula II:

wherein R² is selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl,cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl,cycloalkylaminocarbonyl, arylaminocarbonyl, carboxylakylaminocarbonyl,carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl,alkoxycarbonylcyanoalkenyl and hydroxyalkyl;

wherein R³ is selected from hydrido, alkyl, cyano, hydroxyalkyl,cycloalkyl, alkylsulfonyl and halo; and

wherein R⁴ is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyland heterocyclic; wherein R⁴ is optionally substituted at asubstitutable position with one or more radicals selected from halo,alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl,alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino,alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfamyl,heterocyclic and amino;

provided R² and R³ are not both hydrido; further provided that R² is notcarboxyl or methyl when R³ is hydrido and when R⁴ is phenyl; furtherprovided that R⁴ is not triazolyl when R² is methyl; further providedthat R⁴ is not aralkenyl when R² is carboxyl, aminocarbonyl orethoxycarbonyl; further provided that R⁴ is not phenyl when R² is methyland R³ is carboxyl, and further provided that R⁴ is not unsubstitutedthienyl when R² is trifluoromethyl;

or a pharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula II wherein R² is selected from hydrido, lower alkyl, lowerhaloalkyl, lower alkoxycarbonyl, cyano, lower cyanoalkyl, carboxyl,aminocarbonyl, lower alkylaminocarbonyl, lower cycloalkylaminocarbonyl,arylaminocarbonyl, lower carboxyalkylaminocarbonyl, loweraralkoxycarbonylalkylaminocarbonyl, lower aminocarbonylalkyl, lowercarboxyalkyl, lower alkoxycarbonylcyanoalkenyl and lower hydroxyalkyl;

wherein R³ is selected from hydrido, lower alkyl, cyano, lowerhydroxyalkyl, lower cycloalkyl, lower alkylsulfonyl and halo; and

wherein R⁴ is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyland heterocyclic; wherein R⁴ is optionally substituted at asubstitutable position with one or more radicals selected from halo,lower alkylthio, lower alkylsulfonyl, cyano, nitro, lower haloalkyl,lower alkyl, hydroxyl, lower alkenyl, lower hydroxyalkyl, carboxyl,lower cycloalkyl, lower alkylamino, lower dialkylamino, loweralkoxycarbonyl, aminocarbonyl, lower alkoxy, lower haloalkoxy, sulfamyl,five or six membered hererocyclic and amino; or apharmaceutically-acceptable salt thereof.

A family of specific compounds of particular interest within Formula Iconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

4-[5-(4-(N-ethylaminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-methyl-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N,N-dimethylamino)-3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N,N-dimethylamino)-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N-ethyl-methylamino)-3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-N-ethyl-N-methylamino)-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N,N-diethylamino)-3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(3-chloro-4-(N,N-diethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N,N-diethylamino)-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-fluorophenyl]-N-methylacetamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-chlorophenyl]-N-methylacetamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methylphenyl]-N-methylacetamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-fluorophenyl]-N-methylurea;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-chlorophenyl]-N-methylurea;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methylphenyl]-N-methylurea;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-fluorophenyl]-N-methylthiourea;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-chlorophenyl]-N-methylthiourea;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methylphenyl]-N-methylthiourea;

4-[5-3-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chloro-3-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methyl-3-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl]-N-methylacetamide;

N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-fluorophenyl]-N-methylacetamide;

N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-methylphenyl]-N-methylurea;

N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-fluorophenyl]-N-methylthiourea;

4-[5-(2-(N-ethyl-N-methylamino)-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

N-[2-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-methylphenyl]-N-methylurea;

N-[2-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-fluorophenyl]-N-methylthiourea;

4-[5-(1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(7-fluoro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1-ethyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(7-methyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(7-chloro-1-methyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3-dihydro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(7-fluoro-1-methyl-2,3-dihydro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-aminomethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(N-methylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(N,N-dimethylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-phenyl-3-(N-phenylamino)methyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(N-benzylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(N-benzyl-N-methylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(N-methyl-N-phenylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]acetamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-methylacetamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-phenylacetamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-benzylacetamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]urea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-methylurea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-phenylurea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-benzylurea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]thiourea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-methylthiourea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-phenylthiourea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-benzylthiourea;

4-[4-methoxy-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-methylthio-5-phenyl-3-(triluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-(N-methylamino)-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-(N,N-dimethylamino)-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-methoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-ethoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-phenoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-benzyloxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-methylthio-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-benzylthio-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(N-methylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(N,N-dimethylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(N-benzyl-N-methylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]acetamide;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylacetamide;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylacetamide;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]urea;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylurea;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylurea;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]thiourea;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylthiourea;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylthiourea;

4-[5-phenyl-3-(1,1-difluoro-1-phenylmethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-phenyl-3-(1,1-difluoro-2-phenylethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetic acid;

methyl1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetate;

1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetamide;

N,N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetamide;

N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetamide;

1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-acetic acid;

1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-difluoroaceticacid;

1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-difluoroaceticacid;

1-[4-(aminosulfonyl)phenyl]-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-3-aceticacid;

1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-acetic acid;

(R)-2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]propanoicacid;

(S)-2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]propanoicacid;

(R)-2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazol-3-yl]propanoicacid;

(S)-2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazol-3-yl]propanoicacid;

(R)-2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazol-3-yl]propanoicacid;

(S)-2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazol-3-yl]propanoicacid;

2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-methylpropanoicacid;

2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazol-3-yl]-2-methylpropanoicacid;

2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazol-3-yl]-2-methylpropanoicacid;

2-fluoro-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

3-fluoro-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

2-methyl-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

3-methyl-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

ethyl1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

ethyl1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate;

isopropyl1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-aminophenyl)-1H-pyrazole-3-carboxylate;

1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid;

tert-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

propyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

isobutyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

pentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-nitrophenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-3-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazole-3-carboxylate;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazole-3-carboxylate;

N-[4-methylphenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-[3-chlorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

phenylmethylN-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carbonyl]glycinate;

1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-(4-methoxyphenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-(4-methylphenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N,N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-isopropyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-propyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-isobutyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-tert-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-pentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-cyclohexyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

N-cyclopentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

4-[5-(4-chlorophenyl)-3-(pyrrolidinocarboxamide)l-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(piperidinocarboxamide)-1H-pyrazol-1-yl]benzenesulfonamide;

N-(3-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-(2-pyridyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-(3-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-nitrophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-methylthiophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-carboxamide;

N-methyl1-[4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl-1H-pyrazol-3-yl]carbonyl]glycine;

1-[4-(aminosulfonyl)phenyl]-5-(3-bromo-4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

4-[5-(4-bromophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-cyano-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-cyano-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-cyano-5-(4-methylthiophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-3,5-dichloro-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-bromo-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-nitrophenyl)-3-(cyano)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-bromo-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-bromo-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-bromo-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-cyano-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-fluoro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-4-methylsulfonyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-ethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-ethyl-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-ethyl-5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-ethyl-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-ethyl-5-(3-fluoro-4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-methyl-3-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-bromo-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-bromo-3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-chlorophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-bromo-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

ethyl[1-(4-aminosulfonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylate;

methyl[1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl]carboxylate;

methyl[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylate;

ethyl[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylate;

methyl[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate;

methyl[1-(4-aminosulfonylphenyl)-4-bromo-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate;

methyl[1-(4-aminosulfonylphenyl)-4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazol-3-yl]carboxylate;

methyl[1-(4-aminosulfonylphenyl)-4-chloro-5-(3-dichloro-4-methoxyphenyl)-1H-pyrazol-3-yl]carboxylate;

methyl[1-(4-aminosulfonylphenyl)-5-(3-bromo-4-methoxyphenyl)-4-chloro-1H-pyrazol-3-yl]carboxylate;

[1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl]-carboxamide;

[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxamide;

[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide;

[1-(4-aminosulfonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxamide;

[1-(4-aminosulfonylphenyl)-4-bromo-5-phenyl-1H-pyrazol-3-yl]carboxamide;

[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylicacid;

[1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl]carboxylicacid;

[1-(4-aminosulfonylphenyl)-4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazol-3-yl]carboxylicacid;

4-[4-chloro-3-isopropyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-3-hydroxymethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide;

[1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]propanoicacid;

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,6-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-trifluoromethylphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,5-dimethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-bromo-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-hydroxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluoro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxy-3-(1-propenyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxy-3-propylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,5-difluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-cyclopropylmethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoicacid;

4-[5-(3-methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-amino-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

methyl-4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate;

4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzamide;

4-[5-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4,6-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-fluoro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chloro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dihydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl]phenyl]acetamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl]phenyl]formamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl]phenyl]trifluoroacetamide;

4-[5-(4-[N-methylaminosulfonyl]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-n-butoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-[aminosulfonyl]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3,4-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4,5-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4,5-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,5,6-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3,4,5-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3,4,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3,5,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(pentafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3,4-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,5,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3,4,5-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3,4,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3,5,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-2,3,4,5,6-pentachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-tert-butylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-isobutylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-trifluoromethylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylthiophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(1-morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-phenyl-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dimethylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[1-[4-(aminosulfonyl)phenyl]-3-(difluoromethyl)-1H-pyrazol-5-yl]benzoicacid;

methyl4-[1-[4-(aminosulfonyl)phenyl]-3-(difluoromethyl)-1H-pyrazol-5-yl]benzoate;

4-[1-(4-aminosulfonylphenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzamide;

4-[5-(2-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-cyanophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chloro-3-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dimethoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,5-difluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-bromo-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylsulfonylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1,4-benzodioxan-6-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methylcyclohexyl)-1-H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(methyl-1-cyclohexenyl)-3-(difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-methyl-1-cyclopentenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(benzofuran-2-yl)-3-(difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1,3-benzodioxol-5-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,5-dimethyl-3-furyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-methyl-2-furyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1-chloro-1-methyl-4-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dibromo-4-methylcyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-methoxcyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,4-dimethyl-3-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,5-dichloro-3-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(benzofuran-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-bromo-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-chloro-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-indanyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-methyl-2-thienyl)-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2,3-dihydrobenzofuran-5-yl)-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-benzothienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,4-dihydro-2H-1-benzothiopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-phenylethenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methyl-1,3-benzodioxol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-pyrazinyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(biphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1,2,3,4-tetrahydronaphth-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-thiazolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-oxazolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(cyclohexyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(cyclopentyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(cycloheptyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(1-cyclopentenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(2-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(6-methyl-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-cyclonexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylcyclohex-4-ene-1-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-chloro-2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(5-bromo-2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(6-methoxy-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(chlorodifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methoxyphenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(chlorodifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(phenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(bromodifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(dichloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(dichlorofluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(trichloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(1,1-difluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(1,1-difluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(1,1-dichloroethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(1,1-dichloropropyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-nitro-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(amidino)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(methylsulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-methyl-aminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(imidazolyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(2-pyridyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-cyanoamidino)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(tetrazolyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(phenylsulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-phenylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N,N-dimethylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-methyl-N-phenylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-ethylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-isopropylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-methyl-N-ethylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-methyl-N-(3-chlorophenyl)aminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(N-methyl-N-(2-pyridyl)aminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-isobutyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-hydroxypropyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylphenyl)-3-(2-hydroxyisopropyl)-1H-pyrazol-1-yl]benzenesulfonamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-propanoicacid;

1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-propanoicacid;

1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-propanamide;

methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-propanoate;

4-[3-(3-hydroxymethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(3-hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(3-hydroxymethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-chloro-4-methoxyphenyl)-3-(3-hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

ethyl3-[1-(4-aminosulfonylphenyl)-5-(phenyl)-1H-pyrazol-3-yl]-2-cyano-2-propenoate;

4-[5-(4-chlorophenyl)-3-(chloro)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(bromo)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(fluoro)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-4,5-dihydro-7-methyl-1H-benz[g]indazol-1-yl]benzenesulfonamide;

4-[4,5-dihydro-7-methoxy-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;

4-[4,5-dihydro-3-trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;

4-[4,5-dihydro-7-methyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;

4-[4,5-dihydro-6,8-dimethyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;

4-[(4,5-dihydro-6,8-dimethoxy-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;

methyl[1-(4-aminosulfonylphenyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-3-yl]carboxylate;

4-[4,5-dihydro-3-trifluoromethyl-1H-thieno[3,2,g]indazol-1-yl]benzenesulfonamide;

4-[1-phenyl-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;

4-[1-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;

4-[1-(4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;

4-[1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;

4-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;

4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;

4-[1-(4-fluorophenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;and

4-[1-(4-methoxyphenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide.

A family of specific compounds of particular interest within Formula IIconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;and

4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

The term “hydrido” denotes a single hydrogen atom (H). This hydridoradical may be attached, for example, to an oxygen atom to form ahydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical. Where the term “alkyl” isused, either alone or within other terms such as “haloalkyl” and“alkylsulfonyl”, it embraces linear or branched radicals having one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. More preferred alkyl radicals are “lower alkyl” radicals havingone to about ten carbon atoms. Most preferred are lower alkyl radicalshaving one to about six carbon atoms. Examples of such radicals includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, iso-amyl, hexyl and the like. The term “alkenyl”embraces linear or branched radicals having at least one carbon-carbondouble bond of two to about twenty carbon atoms or, preferably, two toabout twelve carbon atoms. More preferred alkyl radicals are “loweralkenyl” radicals having two to about six carbon atoms. Examples of suchradicals include ethenyl, n-propenyl, butenyl, and the like. The term“halo” means halogens such as fluorine, chlorine, bromine or iodineatoms. The term “haloalkyl” embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1-6 carbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Theterm “hydroxyalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more hydroxyl radicals. More preferred hydroxyalkyl radicals are“lower hydroxyalkyl” radicals having one to six carbon atoms and one ormore hydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms“alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms,such as methoxy radical. More preferred alkoxy radicals are “loweralkoxy” radicals having one to six carbon atoms. Examples of suchradicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Theterm “alkoxyalkyl” also embraces alkyl radicals having two or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals. More pre erred alkoxyalkylradicals are “lower alkoxyalkyl” radicals having one to six carbon atomsand one or two alkoxy radicals. Examples of such radicals includemethoxymethyl, methoxyethyl, ethoxyethyl, methoxybutyl and metoxypropyl.The “alkoxyl” or “alkoxyalkyl” radicals may be further substituted withone o more halo atoms, such as fluoro, chloro or bromo, to provide“haloalkoxy” or “haloalkoxyalkyl” radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy. The term “aryl”, alone or incombination, means a carbocyclic aromatic system containing one, two orthree rings wherein such rings may be attached together in a pendentmanner or may be fused. The term “aryl” embraces aromatic radicals suchas phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The term“heterocyclic” embraces saturated, partially saturated and unsaturatedheteroatom-containing ring-shaped radicals, where the heteroatoms may beselected from nitrogen, sulfur and oxygen. Examples of saturatedheterocyclic radicals include saturated 3 to 6-membered heteromonocylicgroup containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g. thiazolidinyl, etc.]. Examples of partiallysaturated heterocyclic radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole. The term “heteroaryl” embracesunsaturated heterocyclic radicals. Examples of unsaturated heterocyclicradicals, also termed “heteroaryl” radicals include unsaturated 5 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.;unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl,etc.] and the like. The term also embraces radicals where heterocyclicradicals are fused with aryl radicals. Examples of such fused bicyclicradicals include benzofuran, benzothiophene, and the like. Said“heterocyclic group” may have 1 to 3 substituents such as lower alkyl,hydroxy, oxo, amino and lower alkylamino. Preferred heterocyclicradicals include five to ten membered fused or unfused radicals. Morepreferred examples or heteroaryl radicals include benzofuryl,2,3-dihydrobenzofuryl, benzotrienyl, indolyl, dihydroindolyl, chromanyl,benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl,pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. The term“sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. More preferred alkylsulfonyl radicalsare “lower alkylsulfonyl” radicals having one to six carbon atoms.Examples of such lower alkylsulfonyl radicals include methylsulfonyl,ethylsulfonyl and propylsulfonyl. The term “arylsulfonyl” embraces arylradicals as defined above, attached to a sulfonyl radical. Examples ofsuch radicals include phenylsulfonyl. The terms “sulfamyl,”“aminosulfonyl” and “sulfonamidyl,” whether alone or used with termssuch as “N-alkylaminosulfonyl”, “N-arylaminosulfonyl”,“N,N-dialkylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl”, denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂). The terms “N-alkylaminosulfonyl” and“N,N-dialkylaminosulfonyl” denote sulfamyl radicals substitutedrespectively, with one alkyl radical, or two alkyl radicals. Morepreferred alkylaminosulfonyl radicals are “lower alkylaminosulfonyl”radicals having one to six carbon atoms. Examples of such loweralkylaminosulfonyl radicals include N-methylaminosulfonyl,N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl. The terms“N-arylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl” denote sulfamylradicals substituted, respectively, with one aryl radical, or one alkyland one aryl radical. More preferred N-alkyl-N-arylaminosulfonylradicals are “lower N-alkyl-N-arylsulfonyl” radicals having alkylradicals of one to six carbon atoms. Examples of such lowerN-alkyl-N-aryl aminosulfonyl radicals includeN-methyl-phenylaminosulfonyl and N-ethyl-phenylaminosulfonyl The terms“carboxy” or “carboxyl”, whether used alone or with other terms, such as“carboxyalkyl”, denotes —CO₂H. The terms “alkanoyl” or “carboxyalkyl”embrace radicals having a carboxy radical as defined above, attached toan alkyl radical. The alkanoyl radicals may be substituted orunsubstituted, such as formyl, acetyl, propionyl (propanoyl), butanoyl(butyryl), isobutanoyl (isobutyryl), valeryl (pentanoyl), isovaleryl,pivaloyl, hexanoyl or the like. The term “carbonyl”, whether used aloneor with other terms, such as “alkylcarbonyl”, denotes —(C═O)—. The term“alkylcarbonyl” embraces radicals having a carbonyl radical substitutedwith an alkyl radical. More preferred alkylcarbonyl radicals are “loweralkylcarbonyl” radicals having one to six carbon atoms. Examples of suchradicals include methylcarbonyl and ethylcarbonyl. The term“alkylcarbonylalkyl”, denotes an alkyl radical substituted with an“alkylcarbonyl” radical. The term “alkoxycarbonyl” means a radicalcontaining an alkoxy radical, as defined above, attached via an oxygenatom to a carbonyl radical. Preferably, “lower alkoxycarbonyl” embracesalkoxy radicals having one to six carbon atoms. Examples of such “loweralkoxycarbonyl” ester radicals include substituted or unsubstitutedmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl andhexyloxycarbonyl. The term “alkoxycarbonylalkyl” embraces radicalshaving “alkoxycarbonyl”, as defined above substituted to an alkylradical. More preferred alkoxycarbonylalkyl radicals are “loweralkoxycarbonylalkyl” having lower alkoxycarbonyl radicals as definedabove attached to one to six carbon atoms. Examples of such loweralkoxycarbonylalkyl radicals include methoxycarbonylmethyl,tert-butoxycarbonylethyl, and methoxycarbonylethyl. The term“aminocarbonyl” when used by itself or with other terms such as“aminocarbonylalkyl”, “N-alkylaminocarbonyl”, “N-arylaminocarbonyl,“N,N-dialkylaminocarbonyl”, “N-alkyl-N-arylaminocarbonyl”,“N-alkyl-N-hydroxyaminocarbonyl” and“N-alkyl-N-hydroxyaminocarbonylalkyl”, denotes an amide group of theformula —C(═O)NH₂. The terms “N-alkylaminocarbonyl” and“N,N-dialkylaminocarbonyl” denote aminocarbonyl radicals which have beensubstituted with one alkyl radical and with two alkyl radicals,respectively. More preferred are “lower alkylaminocarbonyl” having loweralkyl radicals as described above attached to an aminocarbonyl radical.The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical. The term “aminocarbonylalkyl”embraces alkyl radicals substituted with aminocarbonyl radicals. Theterm “N-cycloalkylaminocarbonyl” denoted aminocarbonyl radicals whichhave been substituted with at least one cycloalkyl radical. Morepreferred are “lower cycloalkylaminocarbonyl” having lower cycloalkylradicals of three to seven carbon atoms, attached to an aminocarbonylradical. The term “aminoalkyl” embraces alkyl radicals substituted withamino radicals. The term “alkylaminoalkyl” embraces aminoalkyl radicalshaving the nitrogen atom substituted with an alkyl radical. The term“amidino” denotes an —C(═NH)—NH₂ radical. The term “cyanoamidino”denotes an —C(═N—CN)—NH₂ radical. The term “heterocyclicalkyl” embracesheterocyclic-substituted alkyl radicals. More preferredheterocyclicalkyl radicals are “lower heterocyclicalkyl” radicals havingone to six carbon atoms and a heterocyclic radical. Examples includesuch radicals as pyrrolidinylmethyl, pyridylmethyl and thienylmethyl.The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferablearalkyl radicals are “lower aralkyl” radicals having aryl radicalsattached to alkyl radicals having one to six carbon atoms. Examples ofsuch radicals include benzyl, diphenylmethyl, triphenylmethyl,phenylethyl and diphenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy. The terms benzyl and phenylmethyl are interchangeable. Theterm “cycloalkyl” embraces radicals having three to ten carbon atoms.More preferred cycloalkyl radicals are “lower cycloalkyl” radicalshaving three to seven carbon atoms. Examples include radicals such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Theterm “cycloalkenyl” embraces unsaturated cyclic radicals having three toten carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl andcycloheptenyl. The term “alkylthio” embraces radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An Example of “alkylthio” is methylthio,(CH₃—S—). The term “alkylsulfinyl” embraces radicals containing a linearor branched alkyl radical, of one to ten carbon atoms, attached to adivalent —S(═O)— atom. The term “aminoalkyl” embraces alkyl radicalssubstituted with amino radicals. More preferred aminoalkyl radicals are“lower aminoalkyl” having one to six carbon atoms. Examples includeaminomethyl, aminoethyl and aminobutyl. The term “alkylaminoalkyl”embraces aminoalkyl radicals having the nitrogen atom substituted withat least one alkyl radical. More preferred alkylaminoalkyl radicals are“lower alkylaminoalkyl” having one to six carbon atoms attached to alower aminoalkyl radical as described above. The terms “N-alkylamino”and “N,N-dialkylamino” denote amino groups which have been substitutedwith one alkyl radical and with two alkyl radicals, respectively. Morepreferred alkylamino radicals are “lower alkylamino” radicals having oneor two alkyl radicals of one to six carbon atoms, attached to a nitrogenatom. Suitable “alkylamino” may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or thelike. The term “arylamino” denotes amino groups which have beensubstituted with one or two aryl radicals, such as N-phenylamino. The“arylamino” radicals may be further substituted on the aryl ring portionof the radical. The term “aralkylamino” denotes amino groups which havebeen substituted with one or two aralkyl radicals, such asN-benzylamino. The “aralkylamino” radicals may be further substituted onthe aryl ring portion of the radical. The terms “N-alkyl-N-arylamino”and “N-aralkyl-N-alkylamino” denote amino groups which have beensubstituted with one aralkyl and one alkyl radical, or one aryl and onealkyl radical, respectively, to an amino group. The terms“N-arylaminoalkyl” and “N-aralkylaminoalkyl” denote amino groups whichhave been substituted with one aryl radicals or one aralkyl radical,respectively, and having the amino group attached to an alkyl radical.More preferred arylaminoalkyl radicals are “lower arylaminoalkyl” havingthe arylamino radical attached to one to six carbon atoms. Examples ofsuch radicals include N-phenylaminomethyl andN-phenyl-N-methylaminomethyl. The terms “N-alkyl-N-arylaminoalkyl”, and“N-aralkyl-N-alkylaminoalkyl” denote N-alkyl-N-arylamino andN-alkyl-N-aralkylamino groups, respectively, and having the amino groupattached to alkyl radicals. The term “acyl”, whether used alone, orwithin a term such as “acylamino”, denotes a radical provided by theresidue after removal of hydroxyl from an organic acid. The term“acylamino” embraces an amino radical substituted with an acyl group. Anexamples of an “acylamino” radical is acetylamino or acetamido(CH₃C(═O)—NH—) where the amine may be further substituted with alkyl,aryl or aralkyl. The term “arylthio” embraces aryl radicals of six toten carbon atoms, attached to a divalent sulfur atom. An example of“arylthio” is phenylthio. The term “aralkylthio” embraces aralkylradicals as described above, attached to a divalent sulfur atom. Anexample of “aralkylthio” is benzylthio. The term “aryloxy” embraces arylradicals, as defined above, attached to an oxygen atom. Examples of suchradicals include phenoxy. The term “aralkoxy” embraces oxy-containingaralkyl radicals attached through an oxygen atom to other radicals. Morepreferred aralkoxy radicals are lower aralkoxy” radicals having phenylradicals attached to lower alkoxy radical as described above. The term“haloaralkyl” embraces aryl radicals as defined above attached tohaloalkyl radicals. The term “carboxyhaloalkyl” embraces carboxyalkylradicals as defined above having halo radicals attached to the alkylportion. The term “alkoxycarbonylhaloalkyl” embraces alkoxycarbonylradicals as defined above substituted on a haloalkyl radical. The term“aminocarbonylhaloalkyl” embraces aminocarbonyl radicals as definedabove substituted on a haloalkyl radical. The term“alkylaminocarbonylhaloalkyl” embraces alkylaminocarbonyl radicals asdefined above substituted on a haloalkyl radical. The term“alkoxycarbonylcyanoalkenyl” embraces alkoxycarbonyl radicals as definedabove, and a cyano radical, both substituted on an alkenyl radical. Theterm “carboxyalkylaminocarbonyl” embraces aminocarbonyl radicalssubstituted with carboxyalkyl radicals, as defined above. The term“aralkoxycarbonylalkylaminocarbonyl” embraces aminocarbonyl radicalssubstituted with aryl-substituted alkoxycarbonyl radicals, as definedabove. The term “cycloalkylalkyl” embraces cycloalkyl radicals havingthree to ten carbon atoms attached to an alkyl radical, as definedabove. More preferred cycloalkylalkyl radicals are “lowercycloalkylalkyl” radicals having cycloalkyl radicals attached to loweralkyl radicals as defined above. Examples include radicals such ascyclopropylmethyl, cyclobutylmethyl, and cyclohexylethyl. The term“aralkenyl” embraces aryl radicals attached to alkenyl radicals havingtwo to ten carbon atoms, such as phenylbutenyl, and phenylethenyl orstyryl.

The present invention comprises a pharmaceutical composition for thetreatment of inflammation and inflammation-associated disorders, such asarthritis, comprising a therapeutically-effective amount of a compoundof Formula I in association with at least onepharmaceutically-acceptable carrier, adjuvant or diluent.

The present invention also comprises a therapeutic method of treatinginflammation or inflammation-associated disorders in a subject, themethod comprising administering to a subject having such inflammation ordisorder a therapeutically-effective amount of a compound of formula I.

Also included in the family of compounds of Formula I are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable sales” embraces salts commonly used to formalkali metal sales and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),mechanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, salicyclic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of formula I include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. All of these salts may be prepared byconventional means from the corresponding compound of Formula I byreacting, or example, the appropriate acid or base with the compound ofFormula I.

GENERAL SYNTHETIC PROCEDURES

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes I-VIII, wherein the R¹-R⁷ substituentsare as defined for Formula I, above, except where further noted.

Synthetic Scheme I shows the preparation of tetrasubstituted pyrazolesfrom starting material 1. In step 1 of synthetic Scheme I, thephenyl-methyl ketone (1) is treated with a base and an alkylatingreagent (R³X, where X represents a leaving group such as tosyl) to givethe substituted ketone (2). In step 2, the substituted ketone (2) istreated with base, such as sodium methoxide, and an acylating reagentsuch as an ester (R²CO₂CH₃), or ester equivalent (R²CO-imidazole, togive the intermediate diketone (3) in a procedure similar to thatdeveloped by Reid and Calvin, J. Amer. Chem. Soc., 72, 2948-2952 (1950).In step 3, the diketone (3) is reacted with a substituted hydrazine inacetic acid or an alcoholic solvent to give a mixture of pyrazoles (4)and (5) Separation of the desired pyrazole (4) can be achieved bychromatography or recrystallization.

Synthetic Scheme II shows the preparation of compounds embraced byFormula I, where R³ is a hydrogen atom. In step 1, ketone (1) is treatedwith a base, preferably NaOMe or NaH, and an ester, or ester equivalent,to form the intermediate diketone (6) which is used without furtherpurification. In step 2, diketone (6) in an anhydrous protic solvent,such as absolute ethanol or acetic acid, is created with thehydrochloride salt or the free base of a substituted hydrazine at refluxfor 10 to 2 hours to afford a mixture or pyrazoles (7) and (8).Recrystallization from diethyl ether/hexane or chromatography affords(7), usually as a light yellow or tan solid.

Synthetic Scheme III shows the procedure for preparation of4,5-dihydrobenz[g]indazole compounds embraced by Formula I. In step 1,ethyl trifluoroacetate is reacted with base, such as 25% sodiummethoxide in a protic solvent, such as methanol, and a 1-tetralonederivative (9) to give the intermediate diketone (10). In step 2, thediketone (10) in an anhydrous protic solvent, such as absolute ethanolor acetic acid, is treated with the free base or hydrochloride salt of asubstituted hydrazine at reflux for 24 hours to afford a mixture ofpyrazoles (11) and (12). Recrystallization gives the4,5-dihydrobenz[g]indazolyl-benzenesulfonamide (11).

Synthetic Scheme IV shows the preparation of pyrazole compounds (13),where R³ is chlorine, from the available pyrazole compounds (7), whereR³ is hydrogen. Chlorination results from passing a stream of chlorinegas at room temperature through a solution containing (7).

Synthetic Scheme V shows the preparation of substituted ketones 18 whichare not commercially available as used in Scheme I. The ketones can beprepared by standard Friedel-Craft acylation of the starting substitutedbenzenes 14 with acid chlorides or anhydrides 15. Alternatively, theketones can be prepared from phenylcarbonitriles 16 by standardorganometallic techniques where M represents metals such as lithium,magnesium, and the like. An alternative organometallic route is shownfrom the aldehydes 17 where M represents metals such as lithium,magnesium, end the like. Oxidation with a suitable oxidizing agent, suchas CrO₃, follows to produce the ketones.

Synthetic Scheme VI shows an alternative regioselective method ofconstructing the pyrazole 21. Commercially available enones 19 can beepoxidized to give epoxyketones 20, which are treated with4-sulfonamidophenylhydrazine hydrochloride to provide the pyrazole 21.

Synthetic Scheme VII shows the preparation of pyrazoles 23 (where R⁴ is3-amino-4-substituted phenyl) from starting material 22. Appropriate5-(4-substituted aryl)pyrazoles can be nitrated next to the R-groupunder standard nitration conditions and the nitro group reduced to theamino group, preferably with hydrazine and Pd/C. The amino compounds canbe further manipulated by alkylation of the amino group.

Synthetic Scheme VIII shows the preparation of pyrazoles 26 from esters24. Reduction of the ester 24 to the alcohol, preferably with lithiumaluminum hydride (LAH) followed by oxidation, preferably with MnO₂,gives the aldehyde 25. Various nucleophiles (such as hydroxamates and1,3-dicarbonyl compounds) can be condensed with the aldehyde to give thedesired oximes or olefins 26.

The following examples contain detailed descriptions of the methods ofpreparation of compounds of Formulas I-II. These detailed descriptionsfall within the scope, and serve to exemplify, the above describedGeneral Synthetic Procedures which form part of the invention. Thesedetailed descriptions are presented for illustrative purposes only andare not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. HRMS is an abbreviation for High resolution massspectrometry. In the following tables, “ND” represents “not determined”.

EXAMPLE 1

4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of4,4,4-Trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dione.

Ethyl trifluoroacetate (23.52 g, 166 mmol) was placed in a 500 mLthree-necked round bottom flask, and dissolved in methyl tert-butylether (75 mL). To the stirred solution was added 25% sodium methoxide(40 mL, 177 mmol) via an addition funnel over a 2 minute period. Next4′-chloroacetophenone (23.21 g, 150 mmol) was dissolved in methyltert-butyl ether 1,20 mL), and added to the reaction dropwise over 5minutes. After stirring overnight (15.75 hours), 3N HCl (70 mL) wasadded. The organic layer was collected, washed with brine (75 mL), driedover MgSO₄, filtered, and concentrated in vacuo to give a 35.09 g ofyellow-orange solid. The solid was recrystallized from iso-octane togive 31.96 g (85%) of the dione: mp 60-67° C.

Step 2: Preparation of4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

4-Sulphonamidophenylhydrazine hydrochloride (982 mg, 4.4 mmol1,1-equivalent) was added to a stirred solution of4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dione from Step 1 (1.00g, 4.0 mmol) in ethanol 150 mL). The reaction was heated to reflux andstirred for 20 hours. (HPLC area percent showed a 96:3 ratio of4-[4-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideto its regioisomer(4-[3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.After cooling to room temperature, the reaction mixture was concentratedin vacuo. The residue was taken up in ethyl acetate, washed with waterand with brine, dried over MgSO₄, filtered, and concentrated in vacuo togive a light brown solid which was recrystallized from ethyl acetate andiso-octane to give the pyrazole (1.28 g, 80%, mp 143-145° C.). HPLCshowed that the purified material was a 99.5:0.5 mixture of4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideto its regioisomer. ¹H NMR (CDCl₃/CD₃OD 10/1) d 5.2 (s, 2H), 6.8 (s,1H), 7.16 (d, j=8.5 Hz, 2H), 7.35 (d, j=8.5 Hz, 2H), 7.44 (d, j=8.66,2H), 7.91 (d, j=8.66, 2H.); ¹³C NMR (CDCl₃/CD₃OD 10/1) d 106.42 (d,j=0.03 Hz), 121.0 (q, j=276 Hz), 125.5, 126.9, 127.3, 129.2, 130.1,135.7, 141.5, 143.0, 143.9 (q, j=37 Hz), 144.0; ¹⁹F NMR (CDCl₃/CD₃OD10/1) d −62.9. EI GC-MS M+=401.

EXAMPLE 2

4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 1-(4-Methylphenyl-4,4,4-trifluorobutane-1,3-dione

4′-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL ofmethanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol(25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours,the mixture was cooled to room temperature and concentrated. 100 mL 10%HCl was added and the mixture extracted with 4×75 mL ethyl acetate. Theextracts were dried over MgSO₄, filtered and concentrated to afford 8.47g (94%) of a brown oil which was carried on without furtherpurification.

Step 2: Preparation of4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

To the dione from Step 1 (4.14 g, 18.0 mmol) in 75 mL absolute ethanolwas added 4.26 g (19.0 mmol) 4-sulphonamidophenylhydrazinehydrochloride. The reaction was refluxed under argon for 24 hours. Aftercooling to room temperature and filtering, the reaction mixture wasconcentrated to afford 6.13 g of an orange solid. The solid wasrecrystallized from methylene chloride/hexane to give 3.11 g (8.2 mmol,46%) of the product as a pale yellow solid: mp 157-159° C.; Anal. calc'dfor C₁₇H₁₄N₃O₂SF₃: C, 53.54; H; 3.70; N, 11.02. Found: C, 53.17; H,3.81; N, 30 10.90.

EXAMPLE 3

4-[5-(3,5-Dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 3,5-Dichloro-4-methoxyacetophenone

To a cooled solution (0° C.) of 7.44 g (55.8 mmol) AlCl₃ in 25 mL ofCH₂Cl₂ under argon was added 2.5 mL of acetic anhydride dropwise. Afterstirring for 0.5 hours, 4.18 g (23.6 mmol) of 2,6-dichloroanisole wasadded dropwise. The reaction was stirred at 0° C. for 1 hour, warmed toroom temperature and stirred for 12 hours. The reaction was poured into5 mL conc. hydrochloric acid/80 mL ice water. The aqueous phase wasextracted with ethyl acetate (3×75 mL). The combined organic washes weredried over MgSO₄, filtered, and stripped to afford the crude product asa yellow oil. NMR analysis showed that acylation only occured para tothe methoxy. The crude oil was used without any further purification.

Steps 2 and 3: Preparation of4-[5-3,5-Dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The title compound was prepared in the same manner as Example 2, Steps 1and 2 and was purified on a prep plate eluting with 10:1 hexane/ethylacetate to afford a yellow solid: Anal. calc'd for C₁₇H₁₂N₃O₃SF₃Cl₂.H₂O:C, 42.16; H, 2.91; N, 8.68. Found: C, 42.03; H, 2.54; N, 8.45.

EXAMPLE 4

4-[5-(3-Ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 3-Ethyl-4-methoxyacetophenone

AlCl₃ (4.9 g, 36.8 mmol) was added to a solution of 2-ethylanisole (2.5g, 18.4 mmol) in methylene chloride (50 mL). Acetyl chloride (1.3 mL,18.4 mmol) was added dropwise to the reaction mixture, which was thenstirred at reflux for 0.5 hours. After cooling to room temperature, thereaction was poured over crushed ice and followed up with a methylenechloride/water extraction. The organic layer was dried over magnesiumsulfate, filtered and concentrated. The crude product waschromatographed on a 4000 micron chromatotron place with 10% ethylacetate/90% hexane as eluant to afford 2.3 g of desired material.

Steps 2 and 3: Preparation of4-[5-(3-Ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The title compound was prepared using the procedure described in Example2, Steps 1 and 2: Anal. calcd for C₁₉H₁₈N₃O₃SF₃: C, 53.64; H, 4.26; N,9.88. Found: C, 53.69; H, 4.36; N, 9.88.

EXAMPLE 5

4-[5-(3-Methyl-4-methylthiophenyl))-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 2-Methylthioanisole

Methyl iodide (0.5 mL, 8.1 mmol) and potassium carbonate (1.1 g, 8.1mmol) were added to a solution of o-thiocresol (1.0 g, 8.1 mmol) in 10mL of DMF. The reaction was stirred at 50° C. for 4 hours and pouredinto hexane and water. The organic layer was separated, dried overmagnesium sulfate and concentrated to afford 1.1 g of desired material.

Steps 2, 3 and 4: Preparation of4-[5-(3-Methyl-4-methylthiophenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The title compound was prepared using the procedures found in Example 4,Steps 1, 2 and 3: Anal. calcd. for C₁₈H₁₆N₃O₂S₂F₂: C, 50.58; H, 3.77; N,9.83. Found: C, 50.84; H, 3.62; N, 9.62.

EXAMPLE 6

4-[5-(3-(3-Propenyl)-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 3-Allyl-4-methoxyacetophenone

Potassium hydroxide (3.2 g, 56.8 mmol) was added to a solution of3-allyl-4-hydroxyacetophenone (10 g, 56.8) in 125 mL THF. Dimethylsulfate (excess) was added and the reaction was stirred at 50° C. for 16hours. The reaction was cooled, concentrated and poured into EtOAc andwater. The organic layer was separated and washed with dilute sodiumhydroxide to get rid of unreacted starting material. The ethyl acetatelayer was dried and concentrated to afford 9.2 g of 3-allyl-4-methoxyacetophenone.

Steps 2 and 3: Preparation of4-[5-(3-(3-Propenyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The title compound was prepared using the procedures described inExample 2, Steps 1 and 2: Anal. calc'd for C₂₀H₁₈N₃F₃O₃S: C, 54.92; H,4.15; N, 9.61. Found: C, 54.70; H, 4.12; N, 9.43.

EXAMPLE 7

4-[5-(3-Propyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 3-n-Propyl-4-methoxyacetophenone

To a solution of the product in Example 6, Step 1 (3 g, 17.0 mmol) in 50mL of ethanol was added a catalytic amount of 4% Pd/C. The reactionmixture was stirred in a Parr shaker at room temperature at 5 psihydrogen for 0.5 hours. The reaction was filtered and concentrated toafford 4 g of pure 3-propyl-4-methoxy acetophenone.

Steps 2 and 3: Preparation of4-[5-(3-n-Propyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The title compound was prepared using the procedures described inExample 2, Steps 1 and 2: Anal. calcd. for C₂₀H₂₀N₃F₃O₃S: C, 54.66; H,4.59; N, 9.56. Found: C, 54.84; H, 4.65; N, 9.52.

EXAMPLE 8

4-[5-(3-Cyclopropylmethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 3-Cyclopropylmethyl-4-methoxyacetophenone

To a solution of the product in Example 6, Step 1 (3 g, 17.0 mmol) andcatalytic Pd(OAc)₂ in 20 mL Et₂O was added ethereal diazomethane untilstarting material was consumed. The reaction was filtered, concentratedand chromatographed on a 4000 micron chromatotron plate (20% EA/80%hexane as eluant) to afford 2.5 g of desired ketone.

Steps 2 and 3: Preparation of4-[5-(3-Cyclopropylmethyl-4-methoxyphenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The title compound was prepared using the procedures described inExample 2, Steps 1 and 2: Anal. calc'd. for C₂₁H₂₀N₃F₃SO₃: C, 55.87; H,4.47; N, 5.31. Found: C, 55.85; H, 4.27; N, 9.30.

EXAMPLE 9

4-[4-Methyl-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

To a solution o the product of Example 2 (500 mg, 1.31 mmol) in 5 mL ofsulfuric acid was added nitric acid (0.6 mL, 1.31 mmol) and the reactionwas stirred at room temperature for 0.5 hours. The mixture was pouredover ice, the solid precipitate was filtered and chromatographed on a4000 micron plate (20% EtOAc/80% hexane as eluant) to afford 410 mg ofdesired material: Anal. calc'd for C₁₇H₁₃N₄O₄SF₃: C, 47.89; H, 3.07; N,13.14. Found: C, 47.86; H, 2.81; N, 13.15.

EXAMPLE 10

4-[5-(3-Amino-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

A catalytic amount of 10% Pd/C was added to a solution of hydrazinehydrate (0.022 mL, 0.7 mmol) in 10 mL of ethanol. The reaction mixturewas refluxed for 15 minutes before the addition of the compound fromExample 9 (100 mg, 0.23 mmol), and the resulting reaction mixture wasrefluxed for another 2 hours. The reaction was cooled, filtered throughCelite and concentrated to afford 100 mg of title compound: Anal. calc'dfor C₁₇H₁₅N₄O₂SF₃.0.5CO₂: C, 50.24; H, 3.61; N, 13.39. Found: C, 50.49;H, 3.44; N, 13.37.

EXAMPLE 11

4-[5-(4-Hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of4-[5-(4-Bromomethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The product from Example 2 (1.13 g, 3.0 mmol) and N-bromosuccinimide(NBS, 0.64 g, 3.6 mmol) were dissolved in 40 mL of benzene andirradiated with a UV lamp for 3 hours. The reaction was cooled to roomtemperature and poured into 50 mL of H₂O. The organic phase wasseparated, washed with brine and dried over MgSO₄. The crude pyrazolewas obtained as an amber oil. The oil was purified via radical bandchromatography eluting with 30% ethyl acetate/70% hexane to afford the4-bromomethyl compound as a yellow oil which crystallized upon standing.

Step 2: Preparation of4-[5-(4-Hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The bromo methyl compound from Step 1 was dissolved in 30 mL ofacetone/4 mL of H₂O and refluxed for 120 hours. The reaction wasconcentrated and the residue dissolved in 50 mL of ethyl acetate anddried over MgSO₄. The crude product was obtained as an amber oil. Theoil was purified via radial band chromatography eluting with 30% ethylacetate/70% hexane to afford the title compound as a yellow solid: Anal.calc'd for C₁₇H₁₄N₃O₃SF₃: C, 51.38; H, 3.55; N, 10.57. Found: C, 51.28;H, 3.59; N, 10.31.

EXAMPLE 12

4-[1-(4-(Aminosulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide

To the product from Example 11 in 2 mL of acetone was added 1.33 M Jonesreagent until an orange color persisted. The reaction was poured into 20mL of ethyl acetate and 20 mL of H₂O and the organic layer separated,washed with saturated sodium bisulfite and dried over MgSO₄. The crudeproduct was filtered through silica gel/Celite to afford the titlecompound as a yellow solid: HRMS m/z 411.0507 (calc'd for C₁₇H₁₂N₃O₄SF₃,411.0500.

The following compounds in Table I were prepared according to proceduressimilar to that exemplified in Examples 1-12, with the substitution ofthe appropiate acetophenone.

TABLE I

M.P. Ex. A (° C.) Analytical 13 4-Br 137-139 Calc. C, 43.07; H, 2.48; N,9.42; Br, 17.91 Obs. C, 43.01; H, 2.32; N, 9.39; Br, 17.62 14 3-Cl154-155 Calc. C, 47.83; H, 2.76; N, 10.46; Cl, 8.82 Obs. C, 47.61; H,2.85; N, 10.31; Cl, 8.43 15 2-Cl 159-160 Calc. C, 47.83; H, 2.76; N,10.46 Obs. C, 47.47; H, 2.65; N, 10.31 16 4-CF₃ 144-145 Calc. C, 46.90;H, 2.55; N, 9.65 Found: C, 46.98; H, 2.57; N, 9.61 17 4-F 168-169 Calc.C, 49.87; H, 2.88; N, 10.90 Found: C, 49.83; H, 2.89; N, 10.86 18 H164-165 Calc. C, 52.31; H, 3.29; N, 11.43 Found: C, 52.14; H, 3.07; N,11.34 19 4-OCH₃ 153-154 Calc. C, 51.38; H, 3.55; N, 10.57 Found: C,51.00; H, 3.48; N, 10.24 20 4-OCF₃ 101-103 Calc. C, 45.24; H, 2.46; N,9.31 Found: C, 45.22; H, 2.37; N, 9.29 21 2-CH₃ 126-128 Calc. C, 53.54;H, 3.70; N, 11.02 Found: C, 53.52; H, 3.55; N, 11.06 22 2,4-di-F 127-130M + H 404 23 2,6-di-F 178-180 M + H 404 24 4-CN   196-197.5 25 3,4-di-Cl145-147 Calc. C, 44.05; H, 2.31; N, 9.63; Cl, 16.25 Found: C, 44.00; H,2.20; N, 9.63; Cl, 16.46 26 2,4-di-Cl 153-155 Calc. C, 43.87; H, 2.35;N, 9.59 Found: C, 43.78; H, 2.13; N, 9.56 27 4-NO₂ 169-172 Calc. C,46.61; H, 2.69; N, 13.59; S, 7.78 (dec) Obs.: C, 46.52; H, 2.67; N,13.51; S, 7.84 28 2-F 165-166 Calc. C, 49.87; H, 2.88; N, 10.90 Found:C, 49.49; H, 2.62; N, 10.79 29 4-NH₂ 124-127 HRMS: 382.0671 (dec) 304-F, 2-CH₃ 170-171 Calc. C, 51.13; H, 3.28; N, 10.52 Found: C, 50.83, H,2.98; N, 10.55 31 3-CH₃ 135-137 Calc. C, 53.54; H, 3.70, N, 11.02 Found:C, 53.15; H, 3.58; N, 10.96 32 4-OCH₂CH₃ 141-142 Calc. C, 51.43; H,4.08; N, 9.99 Found: C, 51.49; H, 3.80; N, 10.08 33 4-OCH₃, 143-144Calc. C, 53.64; H, 4.26; N, 9.87 3,5-di-CH₃ Found: C, 53.49; H, 4.39; N,9.64 34 3-F 143-144 Calc. C, 49.87; H, 2.88; N, 10.90 Found: C, 49.80;H, 2.80; N, 10.84 35 4-OCH₃, 3-F 155-156 Calc. C, 49.16; H, 3.15; N,10.11 Found: C, 48.77; H, 2.93; N, 9.96 36 4-SCH₃ 165-166 Calc. C,49.39; H, 3.41; N, 10.16 Found: C, 49.48; H, 3.46; N, 10.26 37 4-Cl,3-CH₃ ND Calc. C, 49.10; H, 3.15; N, 10.11 Found: C, 49.00; H, 3.00; N,10.10 38 4-CH₂CH₃ ND Calc. C, 54.68; H, 4.08; N, 10.63 Found: C, 54.54;H, 3.73; N, 10.67 39 2,4-di-CH₃ ND Calc. C, 54.68; H, 4.08; N, 10.63Found: C, 54.31; H, 4.32; N, 10.39 40 2-OCH₃ 167-168 Calc. C, 51.38; H,3.55; N, 10.57 Found: C, 51.29; H, 3.34; N, 10.52 41 4-OCH₃, 3-CH₃146-147 42 4-SCH₃, 3-Br 141-144 HRMS: 490.9595 43 4-CH₃, 3-Cl 186-190Calc. C, 49.10; H, 3.15; N, 10.11 Found: C, 49.21; H, 3.17; N, 10.10 443,4-di-OCH₃ 192-193 Calc. C, 50.58; H, 3.77; N, 9.83 Found: C, 50.58; H,3.83; N, 9.72 45 4-OCH₃, 3-Cl 166-168 Calc. C, 47.29; H, 3.03; N, 9.73Found: C, 47.21; H, 2,91; N, 9.55 46 4-OCH₃, 3-Cl, 5-CH₃ ND Calc. C,48.49; H, 3.39; N, 9.42 Found: C, 48.27; H, 3.42; N, 9.22 47 2-OCH₃, 4-F163-164 Calc. C, 49.16; H, 3.15; N, 10.12 Found: C, 49.32; H, 3.27; N,10.18 48 2,4-di-OCH₃ ND Calc. C, 50.58; H, 3.77; N, 9.83 Found: C,50.40; H, 3.78; N, 9.83 49 4-F, 3-Cl ND Calc. C, 45.78; H, 2.40; N,10.01 Found: C, 45.75; H, 2.34; N, 10.15 50 4-OCH₃, 3,5-di-F ND Calc. C,47.12; H, 2.79; N, 9.70 Found: C, 46.72; H, 2.75; N, 9.54 51 4-SCH₃, 3-FND Calc. C, 47.33; H, 3.04; N, 9.74 Found: C, 47.25; H, 3.39; N, 9.45 524-SCH₃, 3-Cl ND Calc. C, 45.59; H, 2.93; N, 9.38 Found: C, 45.56; H,2.76; N, 9.52 53 4-N(CH₃)₂ ND HRMS: 410.1016 54 4-N(CH₂CH₃)₂ ND HRMS:438.1353

EXAMPLE 55

4-[5-(4-Hydroxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

To a solution of the product of Example 41 (240 mg, 0.58 mmol) in DMF (3mL) was added NaSMe (205 mg, 2.9 mmol) and the mixture heated to refluxfor 2 hours. The mixture was cooled, poured into 0.1N HCl and extractedwith EtOAc (3×). The combined extracts were dried over MgSO₄ andconcentrated. Flash chromatography using 1:1 hexane/ethyl acetateprovided 31 mg of the title compound: Anal. calc'd forC₁₇H₁₄N₃O₃SF₃.0.25 H₂O: C, 50.80; H, 3.64; N, 10.45. Found: C, 50.71; H,3.47; N, 10.39.

EXAMPLE 56

4-[5-(4-(N-Methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

To a solution of the products from Example 53 (431 mg, 1.0 mmol) in 10ml methanol was added 36 mg (0.17 mmol) ruthenium (177) chloridehydrate, followed by 1.5 mL 30% hydrogen peroxide (14.7 mmol) over 2hours. The reaction was quenched with 25 mL of 1M in methanol andconcentrated to give 1.24 g of a brown solid. The solid was purified ona prep plate eluting with 2/97/1 methanol/methylene chloride/ammoniumchloride to give 52 mg (0.14 mmol, 12%) of the product as a yellowsolid.

EXAMPLE 57

N-[4-[1-[4-(Aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl]-N-methylacetamide

19 mg (0.051 mmol) of the product from Example 56 was treated with 0.03mL acetic anhydride (0.32 mmol) and 0.03 mL triethylamine (0.22 mmol) in3 mL methylene chloride at room temperrature for 12 hours. The reactionmixtured was concentrated and the residue dissolved in 10 mL ethylacetate. After washing with brine (2×10 mL), the solution was dried overMgSO₄, filtered and concentrated to afford the title compound (18.4 mg,74%) as a yellow solid: HRMS m/e 438.0976 (calc'd for C₁₉H₁₇N₄O₃SF₃,438.0974).

EXAMPLE 58

4-[5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of4,4-Difloro-1-[4-(chloro)phenyl]-butane-1,3-dione.

Ethyl difluoroacetate (24.82 g, 200 mmol) was placed in a 500 mLthree-necked round bottom flask, and dissolved in diethyl ether (200mL). To the stirred solution was added 25% sodium methoxide in methanol(48 mL, 210 mmol) via an additon funnel over a 2 minute period. Next,4′-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether(50 mL), and added to the reaction dropwise over 5 minutes. Afterstirring overnight (18 hours), 1N HCl:250 mL) and ether (250 mL) wereadded. The organic layer was collected, washed with brine (250 mL),dried over MgSO₄, filtered, and concentrated in vacuo to give 46.3 g ofa yellow solid. The solid was recrystallized from methylene chloride andiso-octane to give 31.96 g (69%) of the dione: mp 65-66.5° C.

Step 2: Preparation of4-[5-(4-Chlorophenyl)3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

4-Sulphonamidophenylhydrazine hydrochloride (1.45 g, 6.5 mmol 1.3equivalent) and 4,4-difluoro-1-[4-(chloro)phenyl]butane-1,3-dione fromStep 1 (1.16 g, 5 mmol) were dissolved in ethanol (10 mL). The reactionwas heated to reflux and stirred for 20 hours. After cooling to roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas taken up in ethyl acetate 100 ml), washed with water (100 mL) andwith brine (100 mL), dried over MgSO₄, filtered, and concentrated invacuo to give 1.97 g of a light brown solid which was recrystallizedfrom ethanol and water to give4-[5-(4-Chlorophenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(1.6 g 33%): mp 185-186° C.

EXAMPLE 59

4-[5-(3-Fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 2′-Fluoro-4′-methoxy-acetophenone

Aluminum chloride (30.0 g, 0.6 mol) and chloroform (750 mL) were placein a 2 L three-necked round bottom flask fitted with a mechanicalstirrer and cooled by means of an ice bath. To the stirred solutionacetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining thetemperature between 5-10° C. The mixture was stirred for 10 minutes at5° C. before the dropwise addition at 5-10° C. of 3-fluoroanisole (62.6g 0.5 mol). The mixture was stirred at 0-10° C. for 1 hour and pouredinto ice (1 L). The resultant layers were separated and the aqueouslayer was extracted with dichloromethane (2×250 mL). The combinedorganic layers were washed with water (2×150 ml), dried over anhydrousMgSO₄, filtered and concentrated in vacuo to a volume of 300 mL. Hexaneswere added and a white solid formed which was isolated by filtration andair dried. This material was recrystallized from a mixture ofdichloromethane and hexanes to afford (77.2 g, 92%) of material suitablefor use in the next step: mp 93-94° C.; ¹H NMR (DMSO-d₆) 7.8 (m, 2H),7.3 (t, 1H), 3.9 (s, 3H), 3.5 (s,3H).

Step 2: Preparation of4,4-Difluoro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione.

Ethyl difluoroacetate (4.06 g, 32.7 mmol) was placed in a 250 mlErlenmeyer flask, and dissolved in methyl tert-butyl ether (50 mL). Tothe stirred solution was added 25% sodium methoxide (7.07 g, 32.7 mmol)followed by 3′-fluoro-4′-methoxyacetophenone from Step 1 (5.0 g, 29.7mmol). After stirring for 16 hours, 1N HCl (50 mL) was added. Theorganic layer was collected, washed with water (2×50 mL), dried overanhydrous MgSO₄, filtered, and added to hexanes to precipitate a tansolid (7.0 g, 96%): mp 70-72° C.; ¹H NMR (DMSO-d₆) 8.0 (m, 3H), 7.3 (t,1H), 6.9 (s, 1H), 6.5 (t, 1H), 3.9 (s, 3H).

Step 3: Preparation of4-[5-(3-Fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

4,4-Difluoro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step 2(7.0 g, 28.4 mmol) was dissolved in ethanol (150 mL). To the stirredmixture was added 4-sulphonamidophenylhydrazine hydrochloride (7.4 g, 33mmol) and stirred at reflux overnight (16 hours). The mixture was cooledand water was added until crystals slowly appeared. The product wasisolated by filtration and air dried to provide the desired product as alight tan solid (9.8 g, 87%): mp 159-161° C.; ¹H NMR (DMSO-d₆) 7.85 (d,2H), 7.5 (m, 6H), 7.3-6.9 (m, 5H), 3.8 (s 3H). Anal. Calc'd forC₁₇F₁₄N₃SO₃F₃: C, 51.38; H, 3.55; N, 10.57. Found: C, 51.46; H, 3.52; N,10.63.

EXAMPLE 60

4-[3-Difluoromethyl-5-(4-methoxyphenyl)-1-H-pyrazol-1-yl]benzenesulfonamide

Step 1. Preparation of4,4,4-Trifluoromethyl-1-(4-methoxyphenyl)butane-1,3-dione.

To a stirred solution of 4-mechoxyacetophenone (11.43 g, 76.11 mmol) andethyl difluoroacetate (8.4 mL, 10.4 g, 83.72 mmol) in diethyl ether (300mL) in a 500 mL round bottomed flask was added sodium methoxide inmethanol (18.2 mL of a 25% solution, 79.91 mmol). The solution became adark lavender color within thirty minutes, and then a gray suspensionwithin 1.5 hours. The reaction was stirred for 60 hours. Diethyl ether(300 mL) was added and the mixture was acidified (pH 2) with 1N HCl. Themixture was transferred to a separatory funnel, mixed and separated. Theethereal phase was washed with water, dried over magnesium sulfate, andfiltered. Hexane was added causing precipitation of an orange solid 5.25g of 4,4,4-trifluoromethyl-1-(4-methoxyphenyl) butane-1,3-dione. Anadditional 3.43 g of product was obtained by recrystallization of theconcentrated mother liquor from hexane: ¹H NMR (CDCl₃) 400 mHz 15.58 (brs, 1H), 7.94 (d, J=8.87 Hz, 2H), 6.98 (d, J=8.87 Hz, 3H), 6.49 (s, 1H),6.00 (t, J=54.55 Hz, 1H), 3.89 (s, 3H).

Preparation of4-[5-(4-Methoxyphenyl)-3-difluoromethyl-1-H-pyrazol-1-yl]benzenesulfonamide.

A mixture of 4,4,4-trifluoromethyl-1-(4-methoxyphenyl)butane-1,3-dionefrom Step 1 (2.006 g, 8.79 mmol) and 4-sulfonamidophenylhydrazinehydrochloride salt (2.065 g, 9.23 mmol) dissolved in ethanol (25 mL) washeated to reflux for 16 hours. The reaction was cooled to roomtemperature, was concentrated and recrystallized from methanol yielding4-[5-(4-methoxyphenyl)-3-difluoromethyl-1-H-pyrazol-1-yl]benzenesulfonamideas fluffy can crystals (1.49 g, 45%): mp 133-135° C.; ¹H NMR (CDCl₃) 300mHz 7.90 (d, J=8.863 Hz, 2H), 7 45 (d, J=8.863 Hz, 2H), 7.14 (d, J=8.863Hz, 2H), 6.88 (d, J=8.863 Hz, 2H), 6.77 (t, J=56.47 Hz, 1H), 6. 68 (s,1H), 4.96(br s, 2H), 3.83 (s, 3H); ¹⁹NMR (CDCl₃) 300 mHz −112.70 (d,J=57.9 Hz). High resolution mass spectrum Calc'd for C₁₇H₁₅F₂N₃O₃S:379.0802. Found: 379.0839. Elemental analysis calc'd for C₁₇H₁₅F₂N₃O₃S:C, 53.82; H, 3.99; N, 11.08. Found: C, 53.75; H, 3.99; N, 11.04.

The following compounds in Table II were obtained according toprocedures similar to that exemplified in Examples 58-60, with thesubstitution of the appropriate acetophenone.

TABLE II

M.P. Ex. A (° C.) Anal. 61 4-CF₃ 202-205 M + H 418 62 4-SCH₃ 157-158 634-(1-morpholino) 167-171 M+ 434 64 4-CH₃ 158-159 Calc. C, 56.19; H,4.16; N, 11.56 Obs. C, 56.25; H, 4.17; N, 11.61 65 3,4-di-CH₃ 168-171Calc. C, 57.28; H, 4.54; N, 11.13 Obs. C, 57.34; H, 4.59; N, 11.16 664-CO₂CH₃ 157-158 Calc. C, 53.56; H, 3.09; N, 15.61 Obs. C, 53.45; H,3.11; N, 15.62 67 4-CONH₂ 235-236 HRMS: 393.0833 68 4-CO₂H 258-260 HRMS:394.0662 (dec) 69 2-F, 4-OCH₃ 138-140 Calc. C, 51.38; H, 3.55; N, 10.57Obs. C, 51.14; H, 3.48; N, 10.40 70 4-CN 222-224 Calc. C, 54.54; H,3.23; N, 14.97 Obs.: C, 54.58; H, 3.21; N, 15.06 71 3-Cl, 4-CH₃ 156-158Calc. C, 51.32; H, 3.55; N, 10.56 Obs: C, 51.46; H, 3.53; N, 10.53 723-Cl, 4-OCH₃ 160 Calc. C, 49.34; H, 3.41; N, 10.15; Cl, 8.57; S, 7.75Obs.: C, 49.41; H, 3.37; N, 10.17; Cl, 8.62; S, 7.67 73 4-Cl, 3-CH₃163-165 Calc. C, 51.32; H, 3.55; N, 10.56 Obs.: C, 51.42; H, 3.57; N,10.53 74 3,4-di-OCH₃ 181-185 Calc. C, 52.81; H, 4.19; N, 10.26 Obs.: C,52.86; H, 4.19; N, 10.20 75 3,5-di-Cl, 4-OCH₃ 170-173 Calc. C, 45.55; H,2.92; N, 9.37 Obs.: C, 45.83; H, 3.05; N, 9.31 76 3,5-di-F, 4-OCH₃149-150 Calc. C, 49.16; H, 3.15; N, 10.12 Obs.: C, 49.24; H, 3.16; N,10.13 77 2-OCH₃ 129-132 Calc. C, 53.82; H, 3.99; N, 11.08 Obs.: C,53.82; H, 3.97; N, 11.15 78 3-Br, 4-OCH₃ 164 HRMS: 456.9883 79 4-SO₂CH₃209-210 80 4-C₆H₅ 167-170 M+ 425 81 H 171-172 HRMS: 349.0737

EXAMPLE 82

4-[5-(1,3-Benzodioxol-5-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1. Preparation of(1,3-Benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione.

Ethyl difluoroacetate (1.72 g, 11 mmol) was dissolved in ether (25 mL).To the stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol)followed by 3′,4′-(methylenedioxy)acetophenone (1.64 g, 10 mmol). Afterstirring 16 hours, 1N HCl (25 mL) was added. The organic layer wascollected and washed with water (2×25 mL), dried over magnesium sulfate,filtered, and concentrated. The resulting crude dione was used in thenext step without further purification or characterization.

Step 2. Preparation of5-(1,3-Benzodioxol-5-yl)-4-[3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

1-(1,3-Benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione from Step 1 (2.4g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixturewas added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol)and heated to reflux for 16 hours. The mixture was cooled and water wasadded until crystals slowly appeared. Filtration yielded a light tansolid (3.3 g, 84%): mp 214-218° C.; ¹H NMR (D₆-DMSO): 7.86 (d, J=8.7 Hz,3H), 7.51 (d, J=8.7 Hz, 2H), 7.49 (brs, 2H), 7.3-6.7 (m, 5H, 6.06 s,3H). Anal. Calc'd for C₁₇H₁₃N₃SO₄F₂: C, 51.91; H, 3.33; N, 10.68. Found:C, 51.90; H, 3.25; N, 10.65.

EXAMPLE 83

4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicAcid

Step 1: Preparation of Methyl-4-[4-(chloro)phenyl]-2,4-dioxobutanoate.

Dimethyl oxalate (23.6 g, 200 mmol) was place in a 500 mL three-neckedround bottom flask, and dissolved in diethyl ether (200 mL). To thestirred solution was added 25% sodium methoxide in methanol (48 mL, 210mmol) via an addition funnel over a 2 minute period. Next,4′-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether(50 mL), and added to the reaction dropwise over 3 minutes. Afterstirring overnight (18 hours), 1N HCl (400 mL) and ethyl acetate 750 mL)were added. The organic layer was collected, washed with brine (350 mL),dried over MgSO₄, filtered, and concentrated in vacuo to give 45.7 g ofa yellow solid. The solid was recrystallized from ethyl acetate andiso-octane to give 23 g (48%) of the dione: mp 108.5-110° C.

Step 3: Preparation of4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicAcid.

4-Sulphonamidophenylhydrazine hydrochloride (1.45 g, 6.5 mmol, 1.3equivalent) and methyl-4-[4-(chloro)phenyl-]2,4-dioxobutanoate (1.2 g 5mmol) were dissolved in ethanol (50 mL). The reaction was heated toreflux and stirred for 20 hours. After cooling to room temperature, thereaction mixture was concentrated in vacuo. The residue was taken up inethyl acetate (200 mL) and washed with water (100 mL) and brine (100mL), dried over MgSO₄, filtered and concentrated in vacuo to give 1.7 gof a light brown solid which was recrystallized from methanol and waterto yield 1.6 g (85%) of a white solid. This material was dissolved inmethanol (150 mL) and 3N NaOH (75 mL) and stirred at reflux for 3 hours.The methanol was removed in vacuo and the aqueous solution acidifiedwith concentrated HCl. The product was extracted into ethyl acetate (200mL) which was washed with brine. (100 mL), dried over MgSO₄ filtered andconcentrated to give4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid, 1.4 g (74%): mp 135° C. (dec).

EXAMPLE 84

Methyl1-(4-Aminosulfonylphenyl)-5-(3,5-difluro-4-methoxyphenyl)-1-H-pyrazole-3-carboxylate

Step 1. Preparation of 3,5-Difluro-4-methoxy-acetophenone.

To a stirred suspension of AlCl₃ (24.05 g, 180.40 mmol) in chloroform(300 mL, dried by passage through alumina) at 4° C. (ice bath) undernitrogen was added acetyl chloride (11.0 mL, 152.65 mmol) over 20minutes. This chilled suspension was stirred at 0° C. for 30 minutes and2,6-difluoro anisole was added dropwise over 30 minutes. The resultingsuspension was warmed to room temperature and stirred overnight. Thereaction was quenched by slowly pouring it into a rapidly stirredice/water mixture. The water layer was extracted with methylene chloride(2×50 mL), and the organic phases were combined and concentrated invacuo yielding a clear mobile oil. In a 50 mL round bottomed flask wasadded the above clear oil, DMF (25 mL), K₂CO₃ (15 g). Methyl iodide (6mL) was added and the suspension stirred at 45° C. under nitrogenovernight. Water (1 mL) was added and the mixture was heated for anadditional 14 hours. The crude reaction mixture was cooled to roomtemperature, diluted with water (250 mL) and extracted with diethylether (3×100 mL). The ether phase was washed with sodium bicarbonatesaturated solution, potassium bisulfate (0.1 N solution), dried overMgSO₄, filtered and concentrated in vacuo yielding a clear mobileliquid. This liquid was distilled (30° C., 1 mm) yielding 12.5 g of aclear liquid which was a mixture of 3,5-difluoro-4-methoxyacetophenoneand 3,5-difluoro-4-acetoxyacetophenone in an 85:15 ratio. The yieldbased upon this ratio was 41%. This ketone was used as is.

2. Preparation of Methyl1-(4-Aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyrazole-3-carboxylate.

To a stirred solution of 3,5-difluoro-4-methoxyacetophenone from Step 1(6.46 g, 34.70 mmol) and dimethyl oxalate (6.15 g, 52.05 mmol) inmethanol (80 ml), was added sodium methoxide solution (13.4 mL of 25%solution, 58.99 mmol) in one portion and the reaction stirred overnight.The crude reaction was diluted with methylene chloride, washed withpotassium bisulfate (0.1N solution), brine, dried over MgSO₄, filtered,and concentrated in vacuo yielding methyl4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate as an off writecrystalline solid which was used as is. A mixture of4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate and4-sulfonamidophenylhydrazine hydrochloride salt (7.76 g, 34.70 mmol)dissolved in methanol was warmed to reflux for 9 hours. Upon allowingthe clear reaction to cool to room temperature, a crystallineprecipitate formed which was collected by vacuum filtration yielding5.45 g, (37% based upon the 3,5-difluoro-4-methoxyacetophenone) ofmethyl1-(4-Aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyrazole-3-carboxylateas an off-white solid: mp 185-190° C. ¹H NMR (CDCl₃/300 mHz) 7.95 (d,J=8.86, 2H), 7.49 (d, J=8.86, 2H), 7.02 (s, 1H), 6.77 (m, 2H), 4.99 (s,2H), 4.04 (s, 3H), 3.98 (s, 3H); ¹⁹F NMR (CDCl₃/300 mHz) −126.66. Anal.Calc'd for C₁₇H₁₃F₂N₃O₃S C, 51.06; H, 3.57; N, 9.92Found: C, 51.06; H,3.54, N, 9.99.

EXAMPLE 85

Methyl[1-(4-Aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate

Step 1. Preparation of Methyl 4-[4(Chloro)phenyl]-2,4-dioxobutanoate.

Dimethyl oxalate (15.27 g, 0.129 mol) and 4′-chloroacetophenone (20.0 g,0.129 mol) were charged to a 500 mL round-bottom flask, with provisionsmade for magnetic stirring, and diluted with methanol (300 mL). Sodiummethoxide (25% in methanol, 70 mL) was added in one portion. Thereaction was stirred at room temperature for 16 hours. The reactionbecame an insoluble mass during this time. The solid was mechanicallybroken up, then concentrated hydrochloric acid (70 mL) was added, andthe white suspension was stirred vigorously at room temperature forsixty minutes. The suspension was cooled to 0° C. and held for 30minutes. The soild was filtered, and the filter cake was washed withcold water (100 mL). Upon drying, methyl4-[4-(chloro)phenyl]-2,4-dioxobutanoate was obtained (16.94 g, 54.4%) asthe enol: ¹H NMR (CDCl₃/300 MHz) 7.94 (d, J=8.66 Hz, 2H), 7.48 (d,J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H), 3.48 (s, 1H).

Step 2. Preparation of Methyl[1-(4-Aminosulfonylphenyl]-5-[4-chlorophenyl)-1H-pyrazole-3-yl)carboxylate.

A 100 mL round-bottomed flask equipped with magnetic stirrer andnitrogen inlet was charged with methyl4-[4-(chloro)phenyl]-2,4-dioxobutanoate from Step 1 (5.0 g, 20.78 mmol),4-sulfonamidylphenylhydrazine hydrochloride (5.11 g, 22.86 mmol) andmethanol (50 mL). The reaction vessel was heated to reflux and held for16 hours. A precipitate formed overnight. The suspension was cooled to0° C., held for 0.5 hour, filtered and washed with cold water toprovide, after air-drying, 7.91 g (91%) of crude product. Recrystallized3.50 g from boiling ethanol to yield 3.14 g (97%) of pure methyl(1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl)carboxylate:mp 227° C.; ¹H NMR (CDCl₃/300 MHz) 7.91 (d, J=8.86 Hz, 2H), 7.44 (d,J=8.86 Hz, 2H), 7.33 (d, J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 7.03(s, 1H), 3.96 (s, 3H). Mass Spectrum, MH+=392. Anal. Calc'd forC₁₇H₁₄N₃O₄ClS: C, 52.11; H, 3.60; N, 10.72; Cl, 9.05; S, 9.18. Found: C,52.07; H, 3.07; H, 3.57; N, 10.76; Cl, 9.11; S, 8.27.

EXAMPLE 86

Ethyl[1-(4-Aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate

Methyl(1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)1H-pyrazole-3-yl]carboxylate(Example 85) (0.10 g) was dissolved in absolute ethanol (10 mL and acatalytic amount of 21% NaOEt/EtOH was added. The reaction was stirredwithout temperature control for 72hours, then water (10 mL) was added.The product crystallized, the suspension was cooled to 0° C. and heldfor 30 minutes. The product was filtered, washed with water (5 mL) anddried to yield 0.071 g (70%) of a white solid: Mass Spectrum: MH+=406.Anal. Calc'd for C₁₈H₁₆N₃O₄ClS: C, 53.27; H, 3.97; N, 10.35; Cl, 8.74;S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl, 8.69; S, 7.97.

The following compounds in Table III were prepared according toprocedures similar to that exemplified in Examples 83-86, with thesubstitution of the appropriate reagents.

TABLE III

M.P. Ex. A B (° C.) Analytical 87 4-NO₂ —CH₃ 216-220 MH+ = 403 88 4-F—CH₃ ND Calc. C, 54.40; H, 3.76; N, 11.19; S, 8.54 Obs. C, 54.49; H,3.70; N, 11.25; S, 8.50 89 4-NH₂ —CH₃ 267-269 MH+ = 373 (dec) 90 4-Br—CH₃ 221-224 MH+ = 438 91 4-OCH₃ —CH₃ 169-171 HRMS: 387.0930 92 4-CH₃—CH₃ 213-215 HRMS: 371.0965 93 4-CH₃ —CH₂CH₃ 219-220 Calc. C, 59.21; H,4.97; N, 10.90 Obs. C, 58.73; H, 4.96; N, 10.78 94 4-Cl —CH₂CH₂CH₃ NDCalc. C, 54.35; H, 4.32; N, 10.01; Cl, 8.44; S, 7.64 Obs. C, 54.11; H,4.28; N, 10.14; Cl, 8.54; S, 7.64 95 3,5-di-Cl, 4-OCH₃ —CH₃ 225-229

EXAMPLE 96

4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid (Example 83) (1.08 g, 2.86 mmol), HOBt (0.66 g, 4.3 mmol) and EDC(0.66 g, 3.4 mmol) were dissolved in dimethylformamide (DMF) (20 mL) andstirred at ambient temperature for 5 minutes. To this solution was addedNH₄OH (30%, 2.9 mL) and the reaction stirred for an additional 18 hours.This solution was then poured into ethyl acetate (200 mL) and 1N HCl(200 mL), shaken and separated. The organic Layer was washed withsaturated NaHCC₃ (150 mL) and brine (150 mL), dried over MgSO₄, filteredand concentrated to yield 0.9 g of a white solid which wasrecrystallized from ethyl acetate and iso-octane to yield4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide(0.85 g, 79%): mp 108-110° C.

EXAMPLE 97

[1-(Aminosulfonylphenyl)-5-(4-fluorophenyl-1H-pyrazol-3-yl]carboxamide

A 250 mL three-neck round-bottom flask, equipped with a thermometer, gassparging tube, reflux condenser and provisions for magnetic stirring,was charged withmethyl[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate(Example 88) (3.0 g, 7.99 mmol), methanol (100 mL), and a catalyticamount of sodium cyanide. Anhydrous ammonia gas was sparged through thereaction vessel for 16 hours without temperature control. The suspensionturned a deep red during this time. The reaction was sparged withanhydrous nitrogen at room temperature for 20 minutes, cooled to 0° C.and held for 30 minutes. The solid was filtered and washed with coldwater (50 mL) to yield, upon drying, 1.87 g (65%) of[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamideas a white solid: mp 214-216° C.; ¹H NMR (CDCl₃/CD₃OD/300 MHz) 7.64 (d,J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 6.95 (m, 2H), 6.82-6.67 (m,6H), 6.39 (s, 1H); ¹⁹F NMR (CDCl₃/CD₃OD/282.2 MHz) −112.00 (m). Massspectrum, MH+=361. Anal. Calc'd for C₁₆H₁₃N₄O₃FS: C, 53.33; H, 3.64; N,15.55; S, 8.90. Found: C, 53.41; H, 3.69; N, 15.52; S, 8.96.

EXAMPLE 98

N-(3-Chlorophenyl)-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide

Step 1. Preparation of Methyl 4-[4-Fluorophenyl]-2,4-dioxobutanoate.

Dimethyl oxalate (18.80 g, 0.159 mol) and 4′-fluoroacetophenone (20.0 g,0.145 mol) were charged to a 1000 mL round-bottom flask and diluted withmethanol (400 mL). The reaction flask was placed in a sonication bath(Bransonic 1200), and sodium methoxide (25% in methanol, 70 mL) wasadded over 25 minutes. The reaction was sonicated at 45° C. for 16hours. The reaction became an insoluble mass during this time. The solidwas mechanically broken up, then poured into a hydrochloric acidsolution (1N, 500 mL). A magnetic stirrer was added, and the whitesuspension was stirred vigorously at room temperature for 60 minutes.The suspension was cooled to 0° C. and held for 30 minutes. The solidwas filtered, and the filter cake was then washed with cold water (100mL). Upon drying, methyl 4-[4-fluorophenyl]-2,4-diketobutanoate wasobtained (22.91 g, 70.6%) as the enol: ¹H NMR (CDCl₃/300 MHz) 8.03 (ddd,J=8.86 Hz, J=8.66 Hz, J=5.03 Hz, 2H), 7.19 (dd, J=8.86 Hz, J=8.66 Hz,2H), 7.04 (s, 1H), 3.95 (s, 3H). ¹⁹F NMR (CDCl₃/282.2 MHz) −103.9 (m).

Step 2. Preparation of Methyl4-[-1-(4-Aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate.

A 500 mL one-neck round-bottom flask equipped for magnetic stirring wascharged with methyl 4-[4-fluorophenyl]-2,4-diketobutanoate from Step 1(1.00 mg, 44.61 mmol), 4-sulfonamidylphenylhyrazine hydrochloride (10.98g, 49.07 mmol) and methanol (200 mL). The suspension was heated and heldat reflux for three hours, then cooled to room temperature. Thesuspension was cooled to 0° C., held for 30 minutes, filtered, washedwith water (100 mL), and dried to yield 14.4 g (86%) of methyl4-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylateas a white solid: ¹H NMR (CDCl₃/300 MHz) 7.85 (d, J=8.66 Hz, 2H), 7.36(d, J=8.66 Hz, 2H), 7.18 (ddd, J=8.66 Hz, J=8.46 Hz, J=4.85 Hz, 2H),7.00 (dd, J=8.66 Hz, J=8.46 Hz, 2H), 6.28 (s, 1H), 3.90 (s, 3H). ¹⁹F NMR(CDCl₃/282.2 MHz): −111.4 (m). Mass spectrum, MH+=376. Anal. Calc'd forC₁₇H₁₄N₃O₄FS: C, 54.40; H, 3.76; N, 11.19; S, 8.54. Found: C, 54.49; H,3.70; N, 11.25; S, 8.50.

Step 3. Preparation of[1-(4-Aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylicAcid.

A 500 mL one-neck round-bottom flask, equipped with provisions formagnetic stirring, was charged with methyl4-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylatefrom Step 2 (10.0 g, 26.64 mmol) and tetrahydrofuran (200 mL). Aqueoussodium hydroxide (2.5N, 27 mL) and water (25 mL) were added, and thesuspension was heated to reflux and held for 16 hours. The solids alldissolved during this time. The reaction was cooled to room temperature,and hydrochloric acid solution (1N, 110 mL) was added. The aqueoussuspension was extracted with methylene chloride (2×200 mL). Thecombined organic soultion was dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to an oil. Trituration with 300 mLof methylene chloride yielded, upon filtration and drying, 9.0 g, (94%)of[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxilicacid as a white solid: mp 138-142° C. (dec); ¹H NMR (CD₃OD/300 MHz) 7.93(d, J=8.66 Hz, 2H), 7.51 (d, J=8.66 Hz, 2H), 7.31 (ddd, J=8.86 Hz,J=8.66 Hz, J=4.83 Hz, 2H), 7.11 (dd, J=8.86 Hz, J=8.66 Hz, 2H), 7.06 (s,1H). ¹⁹F NMR (CD₃OD/282.2 MHz): −114.01 (m).

Step 4. Preparation ofN-(3-Chlorophenyl)-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide.

A 100 mL one-neck round-bottom flask, equipped with provisions formagnetic stirring, was charged with[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylicacid from Step 3 (0.500 g, 1.38 mmol), 1-hydroxybenzotriazole hydrate(0.206 g, 1.522 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.318 g, 1.66 mmol) and N,N-dimethylformamide (30 mL).The solution was stirred at room temperature for forty minutes, then3-chloroaniline (0.154 mL, 1.453 mmol) was added. The reaction was heldat room temperature for sixteen hours, then poured into an aqueoussolution of citric acid (5%, 100 mL). The aqueous solution was extractedwith ethyl acetate (2×60 mL), and the combined organic solutions werewashed with aqueous citric acid (60 mL), saturated sodium bicarbonatesolution (2×60 mL) and 50% saturated sodium chloride solution (2×60 mL).The organic solution was dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to an oil. Trituration with 20 mL ofdichloromethane yielded, upon filtration and drying, 0.439 g (67%) ofN-(3-chlorophenyl)-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamideas a white solid: mp 207-212° C.; ¹H NMR (CDCl₃/CD₃OD/300 MHz) 8.90 (s,1H), 7.86 (d, J=8.66 Hz, 2H), 7.79 (t, J=2.01 Hz, 1H), 7.46 (dd, J=7.05Hz, J=2.01 Hz, 1H), 7.33 (d, J=8.86 Hz, 2H), 7.21-7.11 (m, 3H),7.02-6.94 (m, 4H), ¹⁹F NMR (CDCl₃/CD₃OD/282.21 MHz): −111.38 (m). Massspectrum, MH+=470. Anal. Calc'd for C₂₂H₁₆N₄O₃ClFS: C, 56.11; H, 3.42;N, 11.90; Cl, 6.81; S, 7.53. Found: C, 55.95; H, 3.50; N, 11.85; Cl,6.82; S, 7.50.

The following compounds in Table TV were prepared according toprocedures similar to that exemplified in examples 96-98, with thesubstitution of the appropriate starting material.

TABLE IV

M.P. Ex. A B ° C. Analytical  99 4-Br H 143-145 MH+ = 421 100 4-Fphenyl- 233-236 MH+ = 436 101 4-NO₂ H 278-281 MH+ = 387 102 4-F4-CH₃O-phenyl- 209-211 MH+ = 466 103 4-F 4-CH₃-phenyl- 222-225 MH+ = 451104 4-F cyclohexyl- 224-227 MH+ = 442 105 4-F 3-F-phenyl- 227 MH+ = 454106 4-Cl 3-F-phenyl- 174-176 MH+ = 471 (dec) 107 H H ND MH+ = 343 1084-OCH₃, 3-Cl H ND MH+ = 408 109 4-SCH₃ H 115 HRMS: 389.0743 (dec) 1104-OCH₃ H 115-140 Calc. C, 54.83; H, 4.33; N, 15.04 Obs.: C, 54.76; H,4.34; N, 14.98 111 4-CH₃ H 139-140 HRMS H2O: 356.0939 112 4-OCH₃ —CH₃209 MH+ = 387 113 4-Cl glycine benzyl ester 136 MH+ = 525 114 4-Clglycine 124-130 MH+ = 435 115 4-OCH₃, 3-Br H ND M + Li = 457/459 1164-OCH₃, 3,5-di-Cl H 185 HRMS: 440.0113 (dec)

EXAMPLE 117

4-[3-Cyano-5-(4-fluorophenyl-1H-pyrazol-1-yl]benzenesulfonamide

A dry 100 ml three-neck flask, equipped with a reflux condenser,thermometer, pressure-equalizing addition funnel and provisions formagnetic stirring was charged with anhydrous DMF (20 mL) and cooled to0° C. Oxalyl chloride (0.530 mL, 6.105 mmol) was added over twentyseconds, causing a 5° C. exotherm. The white precipitate formeddissolved as the reaction cooled to 0° C. The reaction was held at 0° C.for ten minutes, then a solution of[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide(Example 97) in anhydrous DMF was added to the vigorously stirringsolution over approximately two minutes. After fifteen minutes, pyridine(1.0 mL, 12.21 mmol) was added to quench the reaction. The mixture waspoured into dilute hydrochloric acid (1N, 100 mL) and extracted withethyl acetate (2×75 mL). The combined organic solution was washed with1N HCl (2×100 mL) and with 50% saturated NaCl (3×100 mL). The organicsolution was dried over magnesium sulfate, filtered and concentrated invacuo to a crude oil. The oil was applied to a column of silica gel andeluted with ethyl acetate and hexane (40% ethyl acetate) to obtain, uponconcentration of the appropriate fractions, 0.66 g (69%) of4-[3-cyano-5-(4-fluorophenyl-1H-pyrazol-1-yl]benzenesulfonamide as awrite solid: mp 184-185° C.; ¹H NMR (CDCl₃/300 MHz) 7.94 (d, J=8.86 Hz,2H), 7.44 (d, J=3.86 Hz, 2H), 7.23-7.07 (m, 4H), 6.87 (s, 1H), 4.88(brs, 2H); ¹⁹F NMR (CDCl₃/282.2 MHz) −109.90 (m). Mass spectrum,MH+=343. Anal. Calc'd for C₁₆H₁₁N₄O₂FS: C, 56.14; H, 3.24; N, 16.37; S,9.36. Found: C, 56.19; H, 3.16; N, 16.39; S, 9.41.

The following compounds in Table V were prepared according to proceduressimilar to that exemplified in Example 117, with the substitution of theappropriate starting material.

TABLE V

M.P. Ex. A (° C.) Anal. 118 4-Br 156-157 HRMS: 401.9833 119 4-Cl 142-143120 4-OCH₃ ND HRMS: 354.0774 121 4-CH₃ 90-95 HRMS: 338.0849 122 4-SCH₃192-193 123 4-OCH₃, 3-Cl 179 MH+ = 389 124 4-OCH₃, 3,5-di-Cl 121-125HRMS: 422.0051 125 4-OCH₃, 3-Br 213 MH+ = 433 126 4-NO₂ 230-232 MH+ =370 127 H ND MH+ = 325

EXAMPLE 128

4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of4,4,5,5,6,6,6-Heptafluoro-1-[4-(chloro)phenyl]hexane-1,3-dione.

Ethyl heptafluorobutyrate (5.23 g, 21.6 mmol) was placed in a 100 mLround bottom Flask, and dissolved in ether (20 mL). To the stirredsolution was added 25% sodium methoxide (4.85 g, 22.4 mmol) followed by4-chloroacetophenone (3.04 g, 19.7 mmol). The reaction was stirred atroom temperature overnight (15.9 hours) and treated with 3N HCl (17 mL).The organic layer was collected, washed with brine, dried over MgSO₄,concentrated in vacuo, and recrystallized from iso-octane to give thediketone as a white solid (4.27 g, 62%): mp 27-30° C.; ¹H NMR (CDCl₃)300 MHz 15.20 (br s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz,2H), 6.58 (S, 1H); ¹⁹F NMR (CDCl₃) 300 MHz: −80.94 (t), −121.01 (t),−127.17 (s); M+H 351.

Step 2: Preparation of4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide

The 4-sulfonamidophenylhydrazine hydrochloride (290 mg, 1.30 mmol) wasadded to a stirred solution of the diketone from Step 1 (400 mg, 1.14mmol) in ethanol (5 mL).The reaction was heated to reflux and stirredovernight (23.8 hours). The ethanol was removed in vacuo, and theresidue was dissolved in ethyl acetate, washed with water and brine,dried over MgSO₄, and concentrated in vacuo to give a white solid whichwas passed through a column of silica gel with ethyl acetate/hexane(40%) and recrystallized from ethyl acetate/isooctane to give thepyrazole as a white solid (0.24 g, 42%): mp 168-71° C.; ¹H NMR (CDCl₃)300 MHz 7.90 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 6.79 (s, 1H), 5.20 (br s, 2H); ¹⁹F NMR(CDCl₃) 300 MHz: −80.48 (t), −111.54 (t), −127.07 (s).

EXAMPLE 129

4-[5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of4-Chloro-4,4-difluoro-1-[4-(chloro)phenyl]-butane-1,3-dione.

Methyl 2-chloro-2,2-difluoroacetate (4.20 g, 29 mmol) was placed in a100 mL round bottom flask, and dissolved in ether (10 mL). To thestirred solution was added 25% sodium methoxide (6.37 g, 29 mmol)followed by 4′-chloroacetophenone (4.10 g, 206.5 mmol). The reaction wasstirred at room temperature overnight (20.4 hours), then poured into aseparatory funnel and washed with 3N HCl (15 mL), brine (20 mL), driedover MgSO₄, and concentrated in vacuo and recrystallized from iso-octaneto give the diketone as a yellow solid (3.78 g, 53%): mp 53-55° C.; ¹HNMR (CDCl₃) 300 MHz 14.80 (br s, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.50 (d,J=8.7 Hz, 2H), 6.49 (S, 1H); ¹⁹F NMR (CDCl₃) 300 MHz: −66.03 (s); M+267.

Step 2: Preparation of4-[5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

4-Sulfonamidophenylhydrazine hydrochloride (1.39 g, 6.2 mmol) was addedto a stirred solution of the diketone from Step 1 (1.43 g, 5.7 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred overnight(15.75 hours). The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water and brine, cried overMgSO₄, and concentrated in vacuo to give a white solid which wasrecrystallized from ethyl acetate/isooctane to give the pyrazole as awhite solid (0.32 g, 41%): mp 130-33° C.; ¹H NMR (CDCl₃) 300 MHz 7.90(d, J=8.9 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.19(d, J=8.7 Hz, 2H), 6.76 (s, 1H), 5.13 (br s, 2H); ¹⁹F NMR (CDCl₃) 300MHz: −48.44 (s); M+ 417/419.

EXAMPLE 130

4-[3-(Dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1. Preparation of 3′-Fluoro-4′-methoxy-acetophenone

Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL) were placedin a 2 L three-necked round bottom flask fitted with a mechanicalstirrer and cooled by means of an ice bath. To the stirred solution wasadded acetyl chloride (51.0 g, 0.65 mol) dropwise, maintaining thetemperature between 5-10° C. The mixture was allowed to stir for 10minutes. at 5° C. before the dropwise addition at 5-10° C. of2-fluoroanisole (63.06 g, 0.5 mol).The mixture was stirred at 0-10° C.for 1 hour and poured into ice (1 L). The resultant layers wereseparated and the aqueous layer was extracted with methylene chloride(2×250 mL). The combined organic layers were washed with water (2×150mL), dried over magnesium sulfate, and concentrated to 300 ml. Hexaneswere added and a white solid (77.2 g, 92%) was crystallized from themixture: mp 92-94° C.; ¹H NMR (d₆-DMSO) 7.8 (m, 2H), 7.3 (t, J=8.7 Hz,1H), 3.9 (s, 3H), 2.5 (s, 3H).

Step 2. Preparation of4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione.

Methyl dichloroacetate (1.57 g, 11 mmol) was dissolved ether (25 mL). Tothe stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol)followed by 3′-fluoro-4′-methoxyacetophenone from Step 1 (1.68 g, 10mmol). After stirring 16 hours 1N HCl (25 mL) was added. The organiclayer was collected and washed with water (2×25 mL), dried overmagnesium sulfate, filtered, and concentrated. The resulting crude dionewas used in the next step without further purification orcharacterization.

Step 3. Preparation of4-[3-(dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide.

4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step (2(2.8 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirredmixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11mmol) and heated to reflux for 16 hours. The mixture was cooled andwater was added until crystals slowly appeared. Filtration yielded alight tan solid (2.7 g, 63%): mp 190-193°C.; ¹HNMR (DMSO-d₆) 7.84 (d,J=8.4 Hz, 2H), 7.53 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.47 (brs, 2H),7.3-7.0 (m, 3H), 6.95 (s, 1H), 3.85 (s, 3H). Anal. Calc'd forC₁₇H₁₄N₃SO₃FCl₂: C, 47.45; H, 3.28; N, 9.76. Found: C, 47.68; H, 3.42;N, 10.04.

EXAMPLE 131

4-[3-Fluoromethyl-5-phenyl-1H-pyrazol1-yl]benzenesulfonamide

Step 1: Preparation Methyl 4-Phenyl-2.4-dioxobutanoate

To a solution of dimethyl oxalate (11.81 g, 100 mmol) in ether (200 mL)is added 24 mL of 25% sodium methoxide in methanol, followed by asolution of acetophenone (12.02 g, 100 mmol) in ether (20 mL) and themixture stirred overnight at room temperature. The mixture waspartitioned between 1N HCl and EtOAc and the organic layer was washedwith brine, cried over MgSO₄ and concentrated to give 18.4 g of crudebutanoate.

Step 2: Preparation of Methyl 1-[(4-(Aminosulfonyl) phenyl]-5-phenyl-1Hpyrazole-3-carboxylate

The ester was prepared from the butanoate in Step 1 using the proceduredescribed in Example 2, Step 2.

Step 3: Preparation4-[3-Hydroxymethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide

To a solution of ester in Step 2 (4.0 g, 10.4 mmol) in 50 mL THF wasadded LiAlH₄ (0.592 g, 15.6 mmol) in portions and the mixture refluxedovernight. The reaction was cooled and quenched with 1N NaHSO₄ andextracted with ether (3×). The combined extracts were dried over MgSO₄and concentrated to give 3.5 g crude alcohol. Flash chromatography using1:1 hexane/EtOAc provided the title compound.

Step 4: Preparation4-[3-Fluoromethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide

To a mixture of the alcohol from Step 3 (212 mg, 0.64 mmol) indichloromethane (4 mL) was added diethylaminosulfur trifluoride (0.13mL, 1.0 mmol). The reaction mixture was stirred at room temperature for3 hours and partitioned between water and dichloromethane. The aqueoussolution was extracted with dichloromethane. The organic solution waswashed with brine and concentrated. The residue was chromatographed onsilica (1:1 hexane:ethyl acetate) to give the desired product (72 mg,34%): mp 162-163° C.; Anal. calc'd for C₁₆H₁₄N₃O₂SF: C, 58.00; H, 4.26;N, 12.68. Found: C, 57.95; H, 4.03; N, 12.58.

The following compounds in Table VI were prepared according toprocedures similar to that exemplified in Examples 128-131, with thesubstitution of the appropriate substituted acetyl and acetate startingmaterials.

TABLE VI

M.P. Ex. A R² (° C.) Anal. 132 4-Cl —CF₂CF₃ 145.5-150   133 4-Cl —CH₂Cl198-201 Calc. C, 50.27; H, 3.43; N, 10.99 Found C, 50.34; H, 3.43; N,10.96 134 3-F, 4-OCH₃ —CF₂Cl 120-124 Calc. C, 47.29; H, 3.04; N, 9.74Found C, 47.28; H, 3.37; N, 9.88 135 3-F, 4-OCH₃ —CBrF₂ 120-122 Calc. C,42.87; H, 2.75; N, 8.82 Found C, 42.99; H, 3.81; N, 9.92 136 3-Cl,4-OCH₃ —CH₂Cl ND Calc. C, 49.53; H, 2.84; N, 8.66 Found C, 50.03; H,3.81; N, 9.92

EXAMPLE 137

4-[5-(2-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 4,4,-Difluro-1-(2-pyrazinyl)-butane-1,3-dione.

Ethyl difluoroacetate (2.23 g, 18 mmol) was placed in a 100 mL roundbottom flask and dissolved in ether (10 mL). To the stirred solution wasadded 25% sodium methoxide (4.68 g, 22 mmol) followed by acetylpyrazine(2.00 g,16 mmol). After two hours stirring at room temperature, aprecipitate formed end THF (10 mL) was added to the reaction. Thereaction was stirred an additional 25.9 hours, then treated with 3N HCl(10 mL). The organic layer was collected, washed with brine (20 mL),dried over MgSO₄, and concentrated in vacuo and recrystallized frommethylene chloride/iso-octane to give the diketone as a brown solid(2.23 g, 68%); mp 103-110° C.; ¹H NMR (CDCl₃) 300 MHz 14.00 (br s, 1H),9.31 (d, J=1.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.68 (dd, J=1.4 Hz 2.4Hz, 1H), 7.20 (s, 1H), 6.03 (t, J=54.0 Hz, 1H); ¹⁹F NMR (CDCl₃) 300 MHz:−127.16 (d); M+200.

Step 2: Preparation of4-[5-(2-pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

4-Sulfonamidophenylhydrazine hydrochloride (0.37 g, 1.65 mmol) was addedto a stirred suspension of the diketone from Step 1 (0.30 g, 1.50 mmol)in ethanol (10 mL). The reaction was heated to reflux and stirred for5.3 hours. The ethanol was removed in vacuo, and the residue wasdissolved in ethyl acetate, washed with water (20 mL), brine (20 mL),dried over MgSO₄, and concentrated in vacuo to give a brown solid (0.36g) which was recrystallized from ethyl acetate/ethanol/isooctane to givethe pyrazole as a brown solid (0.20 g, 38%): mp 191-94° C.; ¹H NMR(acetone d₆) 300 MHz 8.94(d, J=1.4 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.52(dd, J=1.4 Hz 2.4 Hz, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz,2H), 7.30 (s, 1H), 7.02 (t, J=54.6 Hz, 1H), 6.73 (br s, 2H): ¹⁹F NMR(acetone d₆) 300 MHz: −113.67 (d); M+351.

EXAMPLE 138

4-[5-(4-Methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 4-methyl-1,3-benzodioxole

11.6 g Adogen 464 and 7 mL of dibromomethane were refluxed in 50 mL ofH₂O for 0.5 hours under argon. 3-Methylcatechol (8.89 g, 71.6 mmol) wasadded over 2 hours and the mixture refluxed for an additional 1 hour.Distillation of the product from the reaction mixture afforded the titlecompound as a yellow oil: HRMS m/e 136.0524 (calc'd for C₈H₈O₂,136.0524).

Step 2: Preparation of 5-acetyl-4-methyl-1,3-benzodioxole (A) and6-acetyl-4-methyl-1,3-benzodioxole (B)

13.8 g of polyphosphoric acid and 5 mL o0 acetic anhydride were heatedto 45° C. under a drying tube of CaSO₄ until liquified. The product fromStep 1 was added and the reaction was stirred at 45° C. for 4.5 hours.The reaction was cooled to room temperature and quenched with 150 mL ofice water. The aqueous phase was washed with ethyl acetate (4×50 mL).The combined organic extracts were dried over MgSO₄ and filtered to givethe crude product as a red oil. The oil was chromatographed on silicagel eluting with 10% ethyl acetate/90% hexane to afford two products: A:Anal. calcd for C₁₀H₁₀O₃: C, 67.07; H, 5.66. Found: C. 67.41, H, 5.75,and B: MS, M+178.

Steps 3 and 4:4-[5-(4-methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The title compound was prepared from product A using the proceduresdescribed in Example 2, Steps 1 and 2: White solid: Anal. calcd forC₁₈H₁₄N₃O₄SF₃: C, 50.82; H, 3.22; N,.9.88. Found: C, 50.71; H, 3.34; N,9.55.

The following compounds in Table VII were prepared according toprocedures similar to that exemplified in Examples 137-138, with thesubstitution of the appropriate starting material.

TABLE VII

M.P. Ex. A B (° C.) Anal. 139 5-bromo-2-thienyl CF₂H 168-169 M + Li440/442 140 2-thienyl CF₂H 190-191 M + Li 367 141 5-chloro-2-thienylCF₂H 168-170 M+ 389/391 142 1-cyclohexenyl CF₂H 160-161 M+ 353 1431,4-benzodioxan CF₂H 115-119 Calc. C, 53.06; H, 3.71; N, 10.32 Obs. C,52.40; H, 3.98; N, 9.96 144 4-methylcyclohex-3-ene-1-yl CF₂H 164-168HRMS: 367.1194 145 2-methylcyclopenten-1-yl CF₂H 165-166 HRMS: 353.1033146 2,5-dimethyl-3-thienyl CF₂H 125-127 Calc. C, 50.12; H, 3.94; N,10.96 Obs. C, 50.21; H, 3.92; N, 11.00 147 2,5-dimethyl-3-furyl CF₂H139-142 Calc. C, 52.31; H, 4.12; N, 11.44 Obs. C, 52.07; H, 4.16; N,11.37 148 5-methyl-2-furyl CF₂H 177-179 Calc C, 50.99; H, 3.71; N, 11.89Obs. C, 51.08; H, 3.68; N, 11.95 149 4-bromo-4-methylcyclohex-1-yl CF₂H175-178 HRMS: 448.0520 (dec) 150 4-methylcyclohex-1-yl CF₂H 190-192HRMS: 369.1341 151 4-chloro-4-methylcyclohex-1-yl CF₂H 197-199 HRMS:403.0958 152 3,4-dibromo-4-methylcyclohex-1-yl CF₂H 172-173 1532-methoxycyclohex-1-yl CF₂H 177-179 HRMS: 386.1357 154 2-benzofuryl CF₂H215-217 Calc C, 55.52; H, 3.37; N, 10.79 Obs. C, 55.52; H, 3.32; N,10.85 155 2,5-dichloro-3-thien-yl CF₂H 154-156 Calc. C, 39.63; H, 2.14;N, 9.90 Obs. C, 39.63; H, 2.13; N, 9.89 156 2-benzofuryl CF₃ 227-228Calc. C, 53.07; H, 2.97; N, 10.31 Obs. C, 53.02; H, 2.96; N, 10.39 1575-chloro-2-thienyl CF₃ 161-165 HRMS: 406.9784 158 5-bromo-2-thienyl CF₃ND Calc: C, 37.18; H, 2.01; N, 9.29; Br, 17.67 Found: C, 37.25; H, 1.93;N, 9.45; Br, 17.40 159 5-indanyl CF₃ 118-120 Calc: C, 56.01; H, 3.96; N,10.31 Found: C, 56.02; H, 4.06; N, 10.22 160 5-methylthien-2-yl CF₃188-190 Calc. C, 46.51; H, 3.12; N, 10.85 Found: C, 46.17; H, 3.10; N,10.75 161 2,3-dihydrobenzofuryl CF₃ 152-153 Calc. C, 52.81; H, 3.45; N,10.26 Found: C, 52.67; H, 3.78; N, 10.13 162 1-cyclohexenyl CF₃ 135-138HRMS: 371.0918 163 6-tetrahydronaphthyl CF₃ 143-145 Calc. C, 57.00; H,4.31; N, 9.97 Found: C, 56.72; H, 4.27; N, 9.90 164 3-benzothienyl CF₃164-165 Calc. C, 51.06; H, 2.86; N, 9.92 Obs. C, 50.96; H, 2.73; N, 9.78165 3,4-dihydrobenzopyranyl CF₃ ND HRMS: 423.0855 166 styryl CF₃ 166-167Calc. C, 54.96; H, 3.59; N, 10.68 Obs. C, 54.77; H, 3.59; N, 10.47 1674-methyl-1,3-benzodioxol-6-yl CF₃ ND Calc. C, 50.82; H, 3.22; N, 9.88Obs. C, 50.64; H, 3.35; N, 9.72 168 3-pyridyl CF₃ 202-204 Calc. C,48.91; H, 3.01; N, 15.21 Obs. C, 48.97; H, 3.16; N, 14.96 1693,4-dihydrobenzothiopyranyl CF₃ ND Calc. C, 51.95; H, 3.67; N, 9.56 Obs.C, 51.98; H, 3.78; N, 9.48

EXAMPLE 170

4-[5-(1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

4-[5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Example 142) (0.31 g, 0.88 mmol) was dissolved in ethanol (15 mL), 10%palladium on charcoal was added, and the suspension was stirred at roomtemperature under hydrogen (36 psi) for 18.25 hours. The reaction wasfiltered through celite, and the ethanol removed in vacuo to give awhite solid, which was recrystallized from methylene chloride/isooctane(0.31 g, 99%): mp 199-203° C.; ¹H NMR (acetone-d₆) 300 MHz 8.05 (d,J=8.7 Hz, 2H), 7.60 (d, J=8.5 Hz,. 2H), 6.69 (t, J=55.0 Hz 1H), 6.47 (s,1H), 5.02 (br s, 2H), 2.67 (m, 1H), 1.71-1.88(m, 5H), 1.24-1.43 (m, 5H);¹⁹F NMR (acetone-d₆) 300 MHz: −112.86 (d).

EXAMPLE 171

4-[5-(4-Chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide

4-[4-(Aminosulfonyl)phenyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid (Example 83) (3.8 g, 10 mmol) and tetrahydrofuran (100 mL) werestirred at room temperature during the dropwise addition of 1.0Mboranetetrahydrofuran complex (30 mL, 30 mmol). The mixture was heatedto reflux for 16 hours. The solution was cooled and methanol was addeddropwise until gas evolution ceased. Ethyl acetate (100 mL) was addedand the mixture was washed successively with 1N hydrochloric acid,brine, sat. aq. sodium bicarbonate solution, and water, dried overmagnesium sulfate, filtered and concentrated. The resultant product wasrecrystallized from ethanol:water to yield 2.6 g (71%) of a white solid:mp 192-194° C.; ¹H NMR (d₆-DMSO/300 MHz) 7.81 (d, J=8.7 Hz, 2H), 7.46(d, J=8.4 Hz, 2H), 7.42 (brs, 2H), 7.40 (d, J=8.7 Hz, 2H), 7.26 (d,J=8.4 Hz, 2H), 6.63 (s, 1H), 5.35 (t, J=8.0 Hz, 1H), 4.50 (d, J=8.0 Hz,2H). Anal. Calc'd for C₁₆H₁₄N₆SO₂Cl: C, 52.82; H, 3.88; N, 11.55. Found:C, 52.91; H, 3.88; N, 11.50.

EXAMPLE 172

4-[5-Phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide

A 60% dispersion of sodium hydride in mineral oil (4.0 g, 100 mmol) wastwice washed with hexane (100 mL each) and dried under a stream ofnitrogen. Ether (300 mL) was added followed by dropwise addition ofethanol (0.25 mL) and γ-butyrolactone (4.0 mL, 52 mmol). The mixture wascooled to 10° C. and acetophenone (5.8 mL, 50 mmol) in ether (40 mL) wasadded dropwise over 1 hour. The mixture was warmed to 25° C. and stirredovernight. The mixture was cooled to 0° C. and quenched with ethanol (5mL) followed by 10% aqueous ammonium sulfate (100 mL). The organicsolution was separated, dried over Na₂SO₄ and concentrated. The residuewas chromatographed on silica gel with 1:1 hexane/ethyl acetate to givethe desired diketone (3.4 g) as an oil. Pyridine (0.34 mL, 4.2 mmol) andthe diketone (700 mg, 3.4 mmol) in methanol (3 mL) were added to aslurry of 4-sulfonamidophenylhydrazine-HCl (750 mg, 3.4 mmol) inmethanol (8 mL). The mixture was stirred at 25° C. overnight andconcentrated in vacuo. The residue was dissolved in methylene chlorideand the solution washed with 1N HCl. The organic solution was separated,dried and concentrated. The residue was chromatographed on silica gelusing ethyl acetate to give the desired pyrazole (435 mg) as a solid:Anal. calc'd for C₁₈H₁₉N₃O₃S: C, 60.49; H, 5.36; N, 11.75. Found: C,60.22; H, 5.63; N, 11.54.

EXAMPLE 173

4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide

Following the procedure of Example 172, but substituting4-fluoroacetophenone for acetophenone afforded4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide.Anal. calc'd for C₁₈H₁₈N₃O₃SF.0.25H₂O: C, 56.90; H, 4.91; N, 11.05.Found: C, 56.80; H, 4.67; N, 11.02.

EXAMPLE 174

4-[4-(Aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole]-3-propanoicAcid

Jones reagent (0.64 mL of a 2.67 M solution) was added dropwise to asolution of4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamidefrom Example 173 (295 mg, 0.78 mmol) in acetone (8 mL). The mixture wasstirred at 25° C. for 2 hours. The solution was filtered and thefiltrate concentrated in vacuo. The residue was dissolved in ethylacetate and washed with water (3×). The organic solution was dried overMgSO₄ and concentrated. The residual oil was crystallized fromether/hexane to give the desired acid (149 mg): mp 180-182° C.: Anal.calc'd for C₁₈H₁₆N₃O₄SF: C, 55.52; H, 4.14; N, 10.79. Found: C, 55.47;H, 4.22; N, 10.50.

EXAMPLE 175

4-(3-Isobutyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide

step 1: Preparation of 2,3-Epoxy-5-methyl-1-phenyl-3-hexanone

To a solution of 5-methyl-1-phenyl-1-hexen-3-one (2.0 g, 10.6 mmol) in15 mL EtOH and 5 mL acetone was added a mixture of 30% hydrogen peroxide(2 mL) and 4 N NaOH (1.5 mL) dropwise and the mixture stirred at 25° C.for 1-3 hours. Water (50 mL) was added and the precipitate filtered anddried at 40° C. in vacuo to provide 1.9 g or the epoxide as a whitesolid: Anal. calc'd for C₁₃H₁₆O₂.0.1H₂O: C, 75.77; H, 7.92. Found: C,75.47; H, 7.56.

Step 2: Preparation of4-(3-Isobutyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide

The epoxide prepared above in Step 1 (1.26 g, 6.11 mmol) and4-sulfonamidophenylhydrazine hydrochloride (1.38 g, 6.17 mmol) werestirred in 20 m EtOH with AcOH (0.5 mL) and the mixture refluxed for 3hours, cooled and quenched with 50 mL H₂O. The aqueous layer wasextracted with ethyl acetate (3×50 mL), the combined extracts were driedover MgSO₄ and concentrated. Flash chromatography using 70:30hexane/ethyl acetate provided the title compound (0.41 g, 19%) as awhite solid: Calc'd for C₁₉H₂₁N₃O₂S: C, 64.20; H, 5.96; N, 11.82. Found:C, 64.31; H, 6.29; N, 11.73.

EXAMPLE 176

Ethyl3-[1-[4-(Aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-cyano-2-propenoate

Step 1: Preparation of4-[3-Formyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide

To a solution of the alcohol prepared in Example 131, Step 3 (1.1 g, 3.3mmol) in ethyl acetate (20 mL) was added MnO₂ (5 g, 60 mmol) and themixture stirred at room temperature overnight. The mixture was filteredthrough Celite and the solution was concentrated to provide the crudealdehyde.

Step 2: Preparation of Ethyl3-[1-[4-(Aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-2-cyano-2-propenoate

To a solution of the aldehyde from Step 1 (1.2 g, 3.6 mmol) in benzene(18 mL) was added ethyl cyanoacetate (0.38 mL, 3.6 mmol), ammoniumacetate (50 mg, 0.7 mmol) and glacial acetic acid (0.17 mL, 2.8 mmol).The solution was heated at reflux for 18 hours, cooled, and partitionedbetween water and ethyl acetate. The organic solution was washed with asaturated aqueous sodium bicarbonate solution, water and brine. Theorganic solution was dried and concentrated. The residue waschromatographed on silica (40% hexane in ethyl acetate) to give thedesired product (1.0 g, 66%): Anal. calc'd for C₂₁H₁₈N₄O₄S: C, 59.82; H,4.30; N, 13.22. Found: C, 59.70; H, 4.29; N, 13.26.

EXAMPLE 177

4-[5-(4-Chlorophenyl)-3-[[(phenylmethoxy)imino]methyl]-1H-pyrazol-1-yl]benzenesulfonamide

To a suspension of 220 mg (0.58 mmol)4-[5-(4-chlorophenyl)-3-formyl-1H-pyrazol-1-yl]benzenesulfonamide(prepared as described in Example 176, Step 1) in dichloromethane (3 mL)was added pyridine (0.12 mL, 1.3 mmol) and O-benzylhyroxylaminehydrochloride (110 mg, 0.68 mmol) and the reaction stirred at roomtemperature for 18 hours. The mixture was partitioned between pH 7buffer and dichloromethane and the organic layer was washed with water,dried and concentrated. Flash chromatography on silica gel (2:1hexane/EtOAc) provided the title compound (151 mg, 56%): mp 158-159° C.:Anal. calc'd for C₂₃H₁₉N₄O₃SCl.0.25H₂O: C, 58.59; H, 4.17; N, 11.88.Found: C, 58.43; H, 4.03; N, 11.85.

The following compounds in Table VIII were prepared according toprocedures similar to that exemplified in Examples 171-177, with thesubstitution of the appropriate starting material.

TABLE VIII

M.P. Ex. A R² (° C.) Anal. 178 H —CH₂OH 183-184 HRMS: 329.0845 1794-OCH₃ —CH₂OH 140-142 Calc. C, 56.81; H, 4.77; N, 11.69 Found: C, 56.92;H, 4.76; N, 11.64 180 3,5-di-Cl, 4-OCH₃ —CH₂OH 191-193 HRMS 427.0199 1813-Cl, 4-OCH₃ —CH₂OH ND Calc. C, 51.84; H, 4.09; N, 10.67 Cl, 9.00; S,8.14 Found: C, 51.77; H, 4.02; N, 10.73; Cl, 9.11; S, 8.03 182 4-CH₃—C(CH₃)₂OH 178-179 183 4-Cl —(CH₂)₂CO₂H 156-159 184 4-Cl —CH₂CONH₂198-200 185 H —CH₃ ND Calc. C, 60.46; H, 5.07; N, 13.21 Found: C, 60.48;H, 4.95; N, 13.19 186 4-Cl —CH₂CN 212-214 Calc. C, 54.77; H, 3.51 N,15.03 Found: C, 54.94; H, 3.61; N, 14.88

EXAMPLE 187

4-[4,5-Dihydro-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide

Step 1: Preparation of 2-Trifluoroacetyl-1-tetralone.

A 250 mL one necked round bottomed flask equipped with a refluxcondenser, nitrogen inlet and provisions for magnetic stirring wascharged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL ofether. To this solution was added 48 mL of 25% sodium methoxide inmethanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50mL of ether was added over about 5 minutes. The reaction mixture wasstirred at room temperature for 14 hours and was diluted wih 100 mL of3N HCl. The phases were separated and the organic layer was washed with3N HCl, and with brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The residue was taken up in 70 mL of boilingethanol/water and cooled to room temperature, whereupon crystals of2-trifluoroacetyl-1-tetralone formed which were isolated by filtrationand air dried to give pure compound (32 g, 81%): mp 48-49° C.; ¹H NMRCDCl₃ δ 2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H),7.50 (m, 1H), 7.98 (m, 1H); ¹⁹F NMR CDCl₃ δ −72.0. EI GC-MS M+=242.

Step 2: Preparation of4-[4,5-Dihydro-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide.

A 100 mL one necked round bottomed flask equipped with reflux condenser,nitrogen inlet and provisions for magnetic stirring was charged with2-trifluoroacetyl-1-tetralone from Step 1 (1.21 g, 5.0 mmol),4-sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mLof absolute ethanol. The solution was warmed to reflux for 15 hours andconcentrated in vacuo. The residue was dissolved in ethyl acetate,washed with water, and with brine, dried over anhydrous MgSO₄, filteredand concentrated in vacuo. The residue was recrystallized from a mixtureof ethyl acetate and isooctane to give 1.40 g, 71% of pure product: mp257-258° C.; ¹H NMR (CDCl₃/CD₃OD, 4:1) δ 2.7 (m, 2H), 2.9 (m, 2H), 6.6(m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m,2H); ¹⁹F NMR (CDCl₃) δ −62.5. FAB-MS M+H=394.

EXAMPLE 188

4-[4,5-Dihydro-7-methyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide

Step 1. Preparation of 6-Methyl-2-(trifluoroacetyl)tetralone.

Ethyl trifluoroacetate (5.33 g, 37.5 mmol) was dissolved in ether (50mL) and treated with a sodium methoxide solution (25% in methanol, 9.92g, 45.9 mmol) followed by 6-methyltetralone (5.94 g, 37.1 mmol). Thereaction was stirred at room temperature for 6.1 hours then treated with3N HCl (20 mL). The organic layer was collected, washed with brine,dried over MgSO₄, and concentrated in vacuo to give a brown oil (8.09 g)that was used in the next step without further purification.

Step 2. Preparation of 4-[4,5-Dihydro-7-methyl-3-yl]benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (1.80 g, 8.0 mmol) was addedto a stirred solution of the diketone from Step 1 (1.86 g, 7.3 mmol) inethanol (10 mL) The reaction was heated to reflux and stirred for 14.8hours. The reaction mixture was cooled and filtered. The filtrate wasconcentrated in vacuo, dissolved in ethyl acetate, washed with water andwith brine, dried over MgSO₄ and reconcentrated in vacuo to give thepyrazole as a brown solid (1.90 g, 64%):

mp 215-218° C. ¹H NMR (acetone-d₆) 300 MHz 8.10 (d, 2H), 7.80 (d, 2H),7.24 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 2H), 6.88 (d, 1H), 3.02 (m, 2H),2.85 (m, 2H), 2.30 (s, 3H). ¹⁹F NMR (acetone-d₆) 282 MHz −62.46 (s).High resolution mass spectrum Calc'd. for C₁₉H₁₇F₃N₃O₂S: 408.0994.Found: 408.0989.

The following compounds in Table IX were prepared according toprocedures similar to that exemplified in Examples 187-188, with thesubstitution of the appropriate ester.

TABLE IX

M.P. Ex. R² R⁶ (° C.) Anal. 189 —CHF₂ 6-OCH₃ 275-277 HRMS: 405.0961 190—CHF₂ 7-CH₃ 240-241 HRMS: 390.1122 191 —CF₃ 6,8-CH₃ 284-288 HRMS:422.1089 192 —CF₃ 7-OCH₃ 277-278 HRMS: 423.0838 193 —CF₃ 7,8-OCH₃269-275 HRMS: 453.1011 194 —CHF₂ 7-OCH₃ 256-257 195 —CO₂CH₃ 7-OCH₃274-276 HRMS: 414.1117

EXAMPLE 196

4-[4,5-Dihydro-3-(trifluoromethyl)-1HThieno[3,2-g]indazol-1-yl]benzenesulfonamide

Step 1. Preparation of 4-Keto-4,5,6,7-tetrahydrothianaphthene.

4-(2-Thienyl)butyric acid (28.42 g, 167 mmol) was placed in a roundbottom flask with acetic anhydride (30 mL) and phosphoric acid (0.6 mL),and heated to reflux for 3.2 hours. The reaction mixture was poured into100 mL of water, extracted with ethyl acetate, washed with brine, driedover MgSO₄, and concentrated in vacuo to give a brown oil (22.60 g)which was vacuum distilled (1 mm Hg, 107-115° C.) to give a white solid(13.08 g, 51%): mp 34-40° C.); ¹H NMR (CDCl₃) 300 MHz 7.29 (d, J=5.2 Hz,1H), 6.99 (d, J=5.2 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H), 2.47 (m, 2H), 2.13(m, 2). M+H=153.

Step 2. Preparation of4-Keto-4,5,6,7-tetrahydro-5-(trifluoroacetyl)thianaphthene.

Ethyl trifluoroacetate (11.81 g, 83.1 mmol) was dissolved in ether (50mL) and treated with a sodium methoxide solution (25% in methanol, 18.35g, 84.9 mmol) followed by 4-keto-4,5,6,7-tetrahydrothianaphthene fromStep 1 (12.57 g, 82.6 mmol) dissolved in ether (25 mL). The reaction wasstirred or 69.4 hours at room temperature, then treated with 3N HCl (40mL). The organic layer was collected, washed with brine, dried overMgSO₄, and concentrated in vacuo to give a brown solid which wasrecrystallized from ether/hexane to give the diketone (10.77 g, 52%) asbrown needles; mp 54-64° C.; ¹H NMR (CDCl₃) 300 MHz 15.80 (s, 1H), 7.41(d, J=5.2 Hz, 1H), 7.17 (d, J=5.2 Hz, 1H), 3.04 (m, 2H), 2.91 (m, 2H);¹⁹F NMR (CDCl₃) 282 MHz −70.37 (s). M+H=249.

Step 3. Preparation of 4-[4,5-Dihydro-3-(trifluoromethyl)-1HThieno[3,2-g]indazol-1-yl]benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (2.36 g, 10.6 mmol) was addedto a stirred solution of the diketone from Step 2 (2.24 g, 9.0 mmol) inethanol (20 mL). The reaction was heated to reflux and stirred 14.7hours. The reaction mixture was filtered and washed with ethanol andwith water to give the desired pyrazole as a white solid (2.69 g, 75%):mp 288-290° C.; ¹H NMR (acetone-d₆) 300 MHz 8.12 (d, J=8.7 Hz, 2H), 7.83(d, J=8.7 Hz, 2H), 7.27 (d, J=5.2 Hz, 1H), 6.81 (br s, 2H), 6.59 (s,J=5.4 Hz, 1H), 3.18 (m, 2H), 3.01 (m, 2H); ¹⁹F NMR (acetone-d₆) 282 MHz−62.46 (s). High resolution mass spectrum Calc'd. for C₁₆H₁₂F₃N₃O₂S₂:399.0323. Found: 399.0280.

EXAMPLE 197

4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzexesulfonamide

Step 1. Preparation of 3-[4-(chloro)phenyl]-propane-1,3-dione.

Ethyl formate (8.15 g, 0.11 mol) and 4′-chloroacetophenone (15.4 g, 0.1mol) were stirred in ether (150 mL) at room temperature. Sodiummethoxide (25%) (23.77 g, 0.11 mol) was added dropwise. The mixture wasstirred at room temperature for 16 hours and was then treated with 150mL of 1N hydrochloric acid. The phases were separated and the etherealsolution washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford 18.3 g of a yellow oil. The resultingcrude mixture was used directly in the next step without purification.

Step 2. Preparation of4-[5-(4-Chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide.

3-[4-(Chloro)phenyl]-propane-1,3-dione from Step 1 (18.3 g, 0.1 mol) and4-sulfonamidophenylhydrazine hydrochloride (22.4 g, 0.1 mol) weredissolved in 150 mL of absolute ethanol and heated to reflux for 16hours. The solution was cooled to room temperature, diluted with 100 mLof water and let stand, whereupon crystals of pyrazole formed that wereisolated by filtration to provide 8.4 g (25%) of a white solid: mp185-187° C.; ¹H NMR (CDCl₃/300 MHz) 7.89 (d, J=8.7 Hz, 2H), 7.76 (d,J=1.8 Hz, 1H), 7.43 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 7.17 (d,J=8.7 Hz, 2H), 6.53 (d. J=1.8 Hz, 1H), 4.93 (brs, 2H). Anal. Calc'd forC₁₅H₁₂N₃SO₂Cl: C, 53.97; H, 3.62; N, 12.59. Found: C, 54.08; H, 3.57; N,12.64.

Step 3. Preparation of4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzensulfonamide

4-[5-(4-Chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide from Step 2(3.0 g, 9 mmol) was dissolved in 50 mL of acetic acid, and 9 mL of 1Mchlorine in acetic acid was added dropwise. The mixture was stirred for16 hours when sat. aq. sodium bicarbonate solution was slowly addeduntil the mixture was neutral to pH paper. The mixture was extractedwith ethyl acetate (3×50 mL), combined and washed with sat. aq. sodiumbicarbonate and with brine, dried over magnesium sulfate, filtered, andconcentrated. The resultant product was recrystallized from isopropanolto yield 2.6 g (78%) of a white solid: mp 168-171° C. (dec); ¹H NMR(DMSO-D₆/300 MHz) 8.08 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7Hz, 2H), 7.46 (brs, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H).Anal Calc'd for C₁₅H₁₁N₃SO₂Cl₂: C, 48.93; H, 3.01; N, 11.41. Found: C,49.01; H, 2.97; N, 11.41.

EXAMPLE 198

4-(4-Fluoro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide

Step 1: Preparation of 2-Fluoroacetophenone

To a solution of 2-hydroxyacetophenone (2.5 g, 18.4 mmol) in 100 mLCH₂Cl₂ at −78° C., was added triflic anhydride (10 g, 35.4 mmol)followed by 2,6-lutidine (4.1 mL, 35.4 mmol) and the mixture stirred at−78° C. for 50 minutes. The mixture was poured into CH₂Cl₂ and water andthe CH₂Cl₂ layer separated, washed with brine, dried over Na₂SO₄ andconcentrated to a peach solid. To a solution of the crude triflate in100 mL THF was added 35 mL of 1N tetrabutylammonium fluoride in THF. Themixture was refluxed for 15 minutes, cooled and poured into ether andwater. The ether layer was separated, washed with brine, dried overNa₂SO₄ and concentrated. Flash chromatography on silica gel using 20:1hexane/EtOAc furnished the α-fluoroketone (0.852 g, 33.5%).

Step 2: Preparation of4-(4-Fluoro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide

A solution of 2-fluoroacetophenone (200 mg, 1.45 mmol) in 2 mLdimethylformamide-dimethylacetal was refluxed for 18 hours. The mixturewas cooled and concentrated to give the crude enaminoketone. Withoutfurther purification, the enaminoketone was treated with4-sulfonamidophenyl hydrazine hydrochloride (0.34 g, 1.52 mmol) in 10 mLEtOH at reflux for 17 hours. The mixture was cooled, filtered and thefiltrate concentrated to a yellow gum. Flash chromatography using agradient of 5:1 to 2:1 hexane/EtoAc provided 0.11 g of a yellow solid:Recrystallization from ether/hexane gave the product as a pale yellowsolid, mp 194-194.5° C.; Anal. calc'd for C₁₅H₁₂N₃O₂SF.0.2H₂O: C, 56.14;H, 3.89; N, 13.09. Found: C, 55.99; H, 3.65; N, 12.92.

EXAMPLE 199

4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide

A 100 mL three-necked round-bottomed flask equipped with refluxcondenser, gas dispersion tube and provisions for magnetic stirring wascharged with4-[5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide(Example 1) (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. Thesolution was stirred at room temperature and treated with a stream ofchlorine gas for a period of 15 minutes. The solution was then stirredat room temperature for 1.25 hours and then diluted with 100 mL ofwater. The solution was then extracted three times with ether and thecombined ethereal phase washed with brine, dried over MgSO₄, filtered,and concentrated in vacuo to give a white solid that was recrystallizedfrom ether/petroleum ether to provide 390 mg (75%) of4-[5-(4-chlorophenyl)-4-chloro-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide:mp 180-182° C.; ¹H NMR (CDCl₃/300 MHz: 7.97 (d, J=6.6 Hz, 2H), 7.49 (d,J=6.3 Hz, 2H), 7.45 (d, J=6.3 Hz, 2H), 7.25 (d, J=6.6 Hz, 2H), 5.78(brs, 2H).

EXAMPLE 200

4-[4-Fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 4,4,4-Trifluoro-1-phenyl-butane-1,3-dione

To a solution of 2-fluoroacetophenone from Step 1 of Example 198 (0.48g, 3.4 mmol) in 25 mL THF at −78° C., was added 1N lithiumbis(trimethylsilyl)amide (4 mL) and the mixture stirred at −78° C. for45 minutes. 1-(Trifluoroacetyl)imidazole (0.65 mL, 5.7 mmol) was addedand the mixture stirred at −78° C. for 30 minutes and at 0° C. for 30minutes. The mixture was quenched with 0.5 N HCl, poured into ether andwater, and the ether layer separated, washed with brine, dried overNa₂SO₄ and concentrated. Flash chromatography on silica gel using agradient of 10:1 to 4:1 hexane/EtOAc furnished the 1,3-diketone (0.34 g,43%).

Step 2: Preparation of4-[4-Fluoro-5-phenyl-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide

The diketone from Step 1 (0.34 g, 1.45 mmol) was treated with4-sulfonamidophenyl hydrazine hydrochloride (0.25 g, 1.56 mmol) in 15 mLEtOH at reflux for 15 hours. The mixture was cooled, filtered and thefiltrate concentrated to a yellow gum. Flash chromatography using 3:1hexane/EtoAc provided 0.28 g of a yellow solid. Recrystallization fromCH₂Cl₂/hexane gave the product as a pale yellow solid: Anal. calc'd forC₁₆H₁₁N₃O₂SF₄: C, 49.87; H, 2.88; N, 10.90. Found: C, 49.79; H, 2.88; N,10.81.

EXAMPLE 201

4-[4-Methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 2-Methyl-1-phenyl-4,4,4-trifluorobutane-1,3-dione

To a solution of propiophenone (965 mg, 7.2 mmol) in THF (20 mL) at −78°C. was added sodium bis(trimethylsilyl)amide (7.9 mL of a 1M solution inTHF). The solution was kept at −78° C. for 0.5 hour and then warmed to−20° C. over 1 hour. The solution was cooled to −78° C. and1-(trifluoroacetyl)imidazole (1.5 g, 9.1 mmol) in THF (4 mL) was addedvia cannula. The solution was warmed to room temperature and stirredovernight. The mixture was partitioned between 1N HCl and ether. Theorganic solution was dried (Na₂SO₄) and concentrated to give the crudediketone (1.9 g).

Step 2: Preparation of4-[4-Methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

The diketone from Step 1 was dissolved in absolute ethanol (25 mL) and4-sulfonamidophenylhydrazine hydrochloride (2.0 g, 9.0 mmol) was added.The mixture was heated at reflux for 19 hours. Volatiles were removed invacuo and the residue dissolved in ethyl acetate. The organic solutionwas washed with water and brine, dried and concentrated. The residue waschromatographed on silica (2:1 hexane/ethyl acetate) to give the titlepyrazole (1.52 g, 49%): mp 145-146° C.; Calc'd for C₁₇H₁₄N₃O₂SF₃: C,53.54; H, 3.70; N, 11.01. Found: C, 53.41; H, 3.66; N, 10.92.

EXAMPLE 202

4-[4-Ethyl-5-(3-methyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 4-Methoxy-3-methylbutyrophenone:

To a suspension of aluminum chloride (10.3 g, 77.2 mmol) indichloromethane (40 mL) at 0° C. was added dropwise a solution of2-methylanisole (5.0 mL, 35.3 mmol) and butyric anhydride (5.8 mL, 35.3mmol). The reaction solution was kept at 0° C. for 2 hours and thenwarmed to room temperature and stirred overnight. The reaction solutionwas poured into conc. HCl (9 mL) and ice water (80 mL). The reaction wasextracted with dichloromethane and the organic layer was washed with 2NNaOH and brine, dried and concentrated. The residue was chromatographedon silica (9:1 hexane:ethyl acetate) to give the desired product (5.2 g,77%).

Step 2 and 3: Preparation of4-[4-Ethyl-5-(3-methyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide:

The title compound was prepared from the butyrophenone in Step 1 usingthe procedure described in Example 201, Steps 1 and 2: mp 135-136° C.;Calc'd for C₂₀H₂₀N₃O₃SF₃: C, 54.66; H, 4.59; N, 9.56. Found: C. 54.11;H, 4.38; N, 9.43.

EXAMPLE 203

4-[4-Cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 2-Cyclopropylacetophenone:

To a suspension of sodium cyanide (1.8 g, 37.0 mmol) in dimethylsulfoxide (20 mL) at 60° C. was added dropwise (bromomethyl)cyclopropane(5.0 g, 37.0 mmol). The addition was done at such a rate to keep thetemperature of the reaction at 60° C. After the addition was completed,the reaction mixture was heated at 80° C. for 15 minutes. The mixturewas cooled and partitioned between ether and water. The organic solutionwas washed with 1N HCl and water, dried and concentrated. The residuewas dissolved in ether (5 mL) and added to a solution of phenylmagnesium bromide (25 mL of a 3M solution in ether) in ether (20 mL) andbenzene (25 mL). The reaction mixture was stirred at room temperaturefor 20 hours, then poured into a 1N HCl solution and stirred for 1.5hours. The organic solution was separated and the aqueous solutionextracted with dichloromethane. The organic solution was dried andconcentrated. The residue was chromatographed on silica (9:1hexane:ethyl acetate) to give the desired product (2.0 g, 34%).

Step 2 and 3: Preparation of4-[4-Cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide:

The title compound was prepared from the acetophenone in Step 1 usingthe procedure described in Example 201), Steps 1 and 2: mp 173-174° C.;Calc'd for C₁₉H₁₆N₃O₂SF₃: C, 56.01; H, 3.96; N, 10.31. Found: C, 55.85;H, 3.78; N, 10.19.

EXAMPLE 204

4-[4-Hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of4-[4-Bromomethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide:

To a solution of4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideprepared in Example 201 (500 mg, 1.3 mmol) in carbon tetrachloride (9mL) and benzene (4 mL) was added N-bromosuccinimide (285 mg, 1.6 mmol).The mixture was irradiated with a sunlamp for 3.5 hours. The reactionmixture was partitioned between dichloromethane and water and theorganic solution was dried and concentrated to give the desired product,412 mg (69%).

Step 2: Preparation of4-[4-Formyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide:

To a solution of the compound prepared in Step 1 (362 mg, 0.79 mmol) indimethyl sulfoxide (7 mL) was added collidine (0.14 mL, 1.0 mmol). Thesolution was heated at 120° C. for 3 hours and then kept at overnight atroom temperature. The reaction solution was partitioned between ethylacetate and water and the organic solution was washed with water, driedand concentrated. The residue was cbromatographed (1:1 hexane:ethylacetate) to give the desired product (205 mg, 66%)

Step 3: Preparation of4-[4-Hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide:

To a solution of the aldehyde prepared in Step 2 (165 mg, 0.41 mmol) inmethanol (3.5 mL) at 0° C. was added sodium borohydride (16 mg, 0.41mmol). The reaction solution was kept at 0° C. for 2.5 hours. Thereaction was quenched with the addition of an aqueous 1M. KHSO₄ solution(3 mL). The mixture was extracted with dichloromethane and the organicsolution dried and concentrated. The residue was chromatographed onsilica (1:1 hexane:ethyl acetate) to give the desired product (36 mg,46%): m.p. 179-180° C.; ¹H NMR d 7.91 (m, 2H), 7.53-7.40 (m, 5H), 6.75(s, 2H), 4.53 (d, 2h, J=5.0 Hz), 4.30 (t, 1H, J=5.0 Hz).

EXAMPLE 205

4-(4-Chloro-3-isobutyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide

To a solution of the pyrazole prepared in Example 175 (0.15 g, 0.42mmol) in CH₂Cl₂ (10 mL) was added an excess of sulfuryl chloride slowlyat room temperature. The mixture was stirred at room temperature for 2hours, quenched with water and the aqueous layer extracted three timewith methylene chloride. The combined organic layers were dried overMgSO₄ and concentrated to give an oil which was purified by flashchromatography on silica gel using 70:30 hexane/ethyl acetate as eluentto give the desired compound: HRMS m/z 389.0970 (calc'd forC₁₉H₂₀ClN₃SO₂, 389.0965).

The following compounds in Table X were prepared according to proceduressimilar to that examplified in Examples 197-205, with the substitutionof the appropriate starting material.

TABLE X

Ex. R³ R² A MP (° C.) Analytical 206 Cl H 4-F 175-176 Calc C, 51.22; H,3,15; N, 11.94 Obs. C, 51.43; H, 3.10; N, 11.82 207 Br H 4-Cl 209-210Calc. C, 43.66; H, 2.69; N, 10.18 Obs. C, 43.74; H, 2.70; N, 10.23 208Cl H H 172-174 Calc. C, 53.98; H, 3.62; N, 12:59 Cl, 10.62; S, 9.60 Obs.C, 54.17; H, 3.64, N, 12.45 Cl, 10.46; S, 9.42 209 Cl H 3,5-di-Cl,4-OCH₃ 211-212 Calc. C, 44.41; H, 2.80; N,  9.71 Obs. C, 44.72; H, 3.04,N,  9.72 210 Br H 4-CH₃ ND HRMS: 391.0003 211 Cl H 4-CH₃ 160-163 Calc.C, 55.25; H, 4.06; N, 12.08 Obs. C, 55.06; H, 4.03, N, 12.02 212 Cl H3-Cl, 4-OCH₃ ND Calc. C, 48.25; H, 3.29; N, 10.55 Cl, 17.80; S, 8.05Obs. C, 48.10; H, 3.31, N, 10.52 Cl, 17.70; S, 7.98 213 Cl H 4-OCH₃155-156 Calc. C, 52.82; H, 3.88; N, 11.55 Obs. C, 52.18; H, 3.93, N,11.41 214 Br H 4-OCH₃ 130-132 215 CN H 4-OCH₃ 216-219 HRMS: 355.0860 216Cl H 3,5-di-r, 4-OCH₃ 198-199 Calc. C, 48.07; H, 3.03; N, 10.51 Obs. C,48.45; H, 3.55, N, 10.10 217 SO₂CH₃ H Cl 182-185 Calc. C, 46.66; H,3.43; N, 10.20 Obs. C, 46.57; H, 3.49. N, 10.39 218 C₂H₅ CF₃ H 177-178Calc. C, 54.68; H, 4.08; N, 10.62 Obs. C, 54.61; H, 4.10; N, 10.54 219CH₃ CF₃ 4-OCH₃ 158-159 Calc. C, 52.55; H, 3.92; N, 10.21 Obs. C, 52.27;H, 4.00; N, 10.16 220 CH₃ CF₃ 4-Cl 154-155 Calc. C, 49.10; H, 3.15; N,10.10 Obs. C, 49.05; H, 3.02; N,  9.96 221 CH₃ CF₃ 4-F 103-104 Calc. C,51.13; H, 3.28; N, 10.52 Obs. C, 51.09; H, 3.26; N, 10.34 222 C₂H₅ CF₃4-Cl ND Calc. C, 50.30; H, 3.52; N,  9.77 Obs. C, 50.40; H, 3.51; N, 9.72 223 CH₃ CF₃ 4-CH₃ 144-145 Calc. C, 54.68; H, 4.08; N, 10.62 Obs.C, 54.38; H, 3.87; N, 10.31 224 C₂H₅ CF₃ 4-CH₃ 142-143 Calc. C, 55.74;H, 4.43; N, 10.26 Obs. C, 55.60; H, 4.37; N, 10.17 225 C₂H₅ CF₃ 4-OCH₃160-161 Calc. C, 53.64; H, 4.26; N,  9.87 Obs. C, 53.55; H, 4.23; N, 9.65 226 C₂H₅ CF₃ 3-F, 4-OCH₃ 156-157 Calc. C, 51.46; H, 3.86; N,  9.47Obs. C, 51.27; H, 3.75; N,  9.33 227 Br CHF₂ 4-Cl 224-226 Calc. C,41.53; H, 2.40; N,  9.08 Obs. C, 41.50; H, 2.38; N,  9.00 228 Cl CHF₂3,5-di-Cl, 4-OCH₃  92-102 Calc C, 42.30; H, 2.51; N,  8.70 (dec) Obs. C,42.50; H, 2.67, N,  8.56 229 Cl CHF₂ H 174-176 Calc. C, 50.07; H, 3.15;N, 10.95 Obs. C, 50.07; H, 3.18, N, 10.98 230 Br CHF₂ H 184-186 Calc C,44.87; H, 2.82; N,  9.81 Obs. C, 44.98; H, 2.81, N,  9.64 231 Cl CHF₂4-OCH₃ 171-172 HRMS: 413.0351 232 Cl CN H 174-177 Calc. C, 53.56; H,3.09; N, 15.61; Cl,  9.98; S, 8.94 (sub) Obs. C, 53.81; H, 3.18; N,15.43; Cl,  9.78; S, 8.91 233 Cl CN 4-Cl ND Calc. C, 48.87; H, 2.56; N,14.25; Cl, 18.03; S, 8.15 Obs. C, 48.99; H, 2.55; N, 14.30; Cl, 17.96;S, 8.08 234 Cl CN 4-F ND Calc. C, 51.00; H, 2.68; N, 14.87; Cl,  9.41;S, 8.51 Obs. C, 51.19; H, 2.73; N, 14.98; Cl,  9.22; S, 8.56 235 Br CN4-F ND Calc. C, 45.62; H, 2.39; N, 13.30; Br, 18.97; S, 7.61 Obs. C,45.51; H, 2.36; N, 13.21; Br, 19.09; S, 7.51 236 Br CN H ND Calc. C,47.66; H, 2.75; N, 13.89; Br, 19.81; S, 7.95 Obs. C, 47.62; H, 2.77; N,13.77; Br, 19.74; S, 8.04 237 Br CO₂C₂H₅ 4-Cl ND HRMS: 482.9707 238 ClCO₂CH₃ H ND HRMS: 342.0495 239 Cl CO₂CH₃ 4-Cl ND HRMS: 426.0128 240 ClCO₂C₂H₅ 4-Cl ND HRMS: 440.0207 241 Cl CO₂CH₃ 4-F ND HRHS: 410.0391 242Br CO₂CH₃ 4-F ND HRMS: 453.9880 243 Cl CO₂CH₃ 4-OCH₃, 3-Cl ND Calc. C,47.38; H, 3.31; N,  9.21; Cl, 15.54; S, 7.03 Obs. C, 47.10; H, 3.26; N, 9.01; Cl, 15.74; S, 6.92 244 Cl CO₂CH₃ 4-OCH₃, 3,5-di-Cl 198-199 Calc.C, 44.06; H, 2.88; N,  8.56. Obs. C, 43.59; H, 2.77; N,  8.44 245 ClCO₂CH₃ 4-OCH₃, 3-Br ND Calc. C, 43.18, H, 3.02; N,  8.39; S, 6.40 Obs.C, 43.25; H, 2.97; N,  8.40; S, 6.59 246 Cl CONH₂ H ND HRMS: 377.0539247 Cl CONH₂ 4-Cl ND HRMS: 411.0115 248 Cl CONH₂ 4-F ND HRMS: 395.0397249 Br CONH₂ 4-F ND Calc. C, 43.75, H, 2.75; N, 12.75; Br, 18.19; S,7.30 Obs. C, 43.65; H, 2.78; N, 12.66; Br, 18.13; S, 7.21 250 Br CO₂H HND HRMS: 419.9920 251 Cl CO₂H H ND HRMS 377.0249 252 Cl CO₂H 4-Cl NDCalc. C, 46.62, H, 2.69; N, 10.19; Cl, 17.20; S, 7.78 Obs. C, 46.59, H,2.68; N, 10.21; Cl, 17.25; S, 7.73 253 Cl CO₂H 4-OCH₃, 3,5-di-Cl 220(dec) Calc. C, 42.83; H, 2.54; N,  8.81 Obs. C, 43.65; H, 2.52; N,  8.78254 Cl CH₃ H ND Calc. C, 55.25; H, 4.06; N, 12.08 Obs. C, 55.24; H,4.26; N, 12.17 255 Cl CH₂OH H 195-197 HRMS: 363.0431 256 Cl CH₂OH 4-Cl203-204 Calc. C, 48.25; H, 3.29; N, 10.55 Obs. C, 48.36; H, 3.27; N,10.50 257 Cl (CH₂)₂CO₂H 4-Cl 212-214 Calc. C, 49.10; H, 3.43; N,  9.54Obs. C, 49.23; H, 3.45; N,  9.49 258 OCH₃ CF₃ H 137-138 Calc. C, 51.38;H, 3.55; N, 10.57 Obs. C, 51.40; H, 3.47; N, 10.47

EXAMPLE 259

4-[4-Chloro-3-cyano-5-[4-(fluoro)phenyl])-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]benzenesulfonamide

Increasing the polarity of the eluant used in the purification inExample 234 to 60% ethyl acetate, upon concentration of the appropriatefractions, yielded4-[4-chloro-3-cyano-5-[4-(fluoro)phenyl])-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]benzenesulfonamide(0.485 g, 15%): High Resolution Mass Spectrum (MLi+) calc'd: 438.0779.Found: 438.0714. Elemental analysis calc'd for C₁₉H₁₅N₅O₂FClS: C, 52.84:H, 3.50: N, 16.22; Cl, 8.21; S, 7.42. Found: C, 52.76; H, 3.52; N,16.12; Cl, 8.11; S, 7.35.

EXAMPLE 260

4-[4-Bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]benzenesulfonamide

Similarly,4-[4-bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]benzenesulfonamidewas isolated from the purification of Example 235 (0.153 g, 28%): HighResolution Mass Spectrum (M+) calc'd: 457.0208. Found: 457.0157.Elemental analysis calc'd for C₁₉H₁₆N₅O₂BrS: C, 49.79: H, 3.52: N,15.28; Br, 17.43; S, 6.99. Found: C, 49.85; H, 3.56; N, 15.10; Br,17.52; S, 6.87.

EXAMPLE 261

4-[1-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide

Step 1: Preparation ofN,N-bis(4-Methoxybenzyl)-4-(aminosulfonyl)acetophenone.

To a solution of 4-(aminosulfonyl)acetophenone (2.0 g, 9.0 mmol) indimethylsulfoxide (25 mL) was added sodium hydride (450 mg, 19.0 mmol).The reaction mixture was stirred for 45 minutes and then 4-methoxybenzylbromide (3.5 g, 19.0 mmol) in dimethylsulfoxide (5 mL) was added viacannula. The mixture was stirred at room temperature for 24 hours andpartitioned between ethyl acetate and pH 7 buffer. The aqueous solutionwas extracted with ethyl acetate. The organic solution was dried (MgSO₄)and concentrated. The residue was chromatographed on silica (2:1hexane:ethyl acetate) to give the desired product (815 mg, 21%).

Step 2: Preparation ofN,N-bis(4-Methoxybenzyl)-4-[1-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzenesulfonamide

To a 25% sodium methoxide solution in methanol (0.2 mL) was added ethyltrifluoroacetate (75 mg, 0.53 mmol) and the protected acetophenone fromStep 1 (235 mg, 0.53 mmol). THF (0.5 mL) was added and the reactionmixture was heated at reflux for 2 hours and then stirred at roomtemperature overnight. The mixture was partitioned between ether and 1NHCl solution. The organic solution was dried and concentrated to givethe crude diketone (279 mg), which was diluted with absolute ethanol(2.5 mL). To this slurry was added pyridine (49 mg, 0.62 mmol) and4-fluorophenylhydrazine hydrochloride (80 mg, 0.50 mmol). The mixturewas stirred at room temperature for 24 hours and concentrated in vacuo.The residue was dissolved in methylene chloride and washed with 1N HCl.The organic solution was dried and concentrated. The residue waschromatographed on silica (3:1 hexane:ethyl acetate) to give theprotected pyrazole (159 mg, 51%).

Step 3: Preparation of4-[1-(4-Fluorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzenesulfonamide.

To a solution of the protected pyrazole (50 mg, 0.08 mmol) inacetonitrile (1 mL) and water (0.3 mL) was added ceric ammonium nitrate(360 mg, 0.65 mmol). The reaction solution was kept at room temperaturefor 16 hours. The solution was poured into water (15 mL) and extractedwith ethyl acetate (2×25 mL). The combined extracts were dried (MgSO₄)and concentrated. The residue was chromatographed on silica (2:1hexane:ethyl acetate) to give the desired product (13 mg, 42%): ¹H NMR(CD₃OD) 7.88 (d,2H), 7.46 (d, 2H), 7.39 (dd, 2H), 7.21 (t, 2H), 7.06 (s,1H).

EXAMPLE 262

4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide

The title compound was prepared using the procedure described in Example261: HRMS m/z 397.0702 (calc'd for C₁₇H₁₄N₃O₃SF₃, 397.0708).

BIOLOGICAL EVALUATION Rat Carrageenan Foot Pad Edema Test

The carrageenan foot edema test was performed with materials, reagentsand procedures essentially as described by Winter, et al., (Proc. Soc.Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats wereselected in each group so that the average body weight was as close aspossible. Rats were fasted with free access to water for over sixteenhours prior to the test. The rats were dosed orally (1 mL) withcompounds suspended in vehicle containing 0.5% methylcellulose and0.025% surfactant, or with vehicle alone. One hour later a subplantarinjection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% salinewas administered and the volume of the injected foot was measured with adisplacement plethysmometer connected to a pressure transducer with adigital indicator. Three hours after the injection of the carrageenanthe volume of the foot was again measured. The average foot swelling ina group of drug-treated animals was compared with that of a group ofplacebo-treated animals and the percentage inhibition of edema wasdetermined (Otterness and Bliven, Laboratory Models for Testing NSAIDS,in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)).The % inhibition shows the % decrease from control paw volume determinedin this procedure and the data for selected compounds in this inventionare summarized in Table I.

Rat Carrageenan-induced Analgesia Test

The analgesia test using rat carrageenan was performed with materials,reagents and procedures essentially as described by Hargreaves, et al.,(Pain, 32, 77 (1988) Male Sprague-Dawley rats were treated as previouslydescribed for the Carrageenan Foot Pad Edema test. Three hours after theinjection of the carrageenan, the rats were placed in a specialplexiglass container with a transparent floor having a high intensitylamp as a radiant heat source, positionable under the floor. After aninitial twenty minute period, thermal stimulation was begun on eitherthe injected foot or on the contralateral uninjected foot. Aphotoelectric cell turned off the lamp and timer when light wasinterrupted by paw withdrawal. The time until the rat withdraws its rootwas then measured. The withdrawal latency in seconds was determined forthe control and drug-treated groups, and percent inhibition of thehyperalgesic foot withdrawal determined. Results are shown in Table XI.

TABLE XI RAT PAW EDEMA ANALGESIA % Inhibition @ % Inhibition @ Examples10 mg/kg body weight 30 mg/kg body weight  1 44 94  2 35 38 58 36 65 5925 41 60 49 39 82  22* 86  42* 98  2* 117  32 129   47* 170   18* 171 14 37 188   32* 197   45* 27 199  35 *Assay performed at 30 mg/kg bodyweight

Evaluation of COX I and COX II Activity in vitro

The compounds of this invention exhibited inhibition in vitro of COX I.The COX II inhibition activity of the compounds of this inventionillustrated in the Examples was determined by the following methods.

a. Preparation of Recombinant COX Baculoviruses

A. 2.0 kb fragment containing the coding region of either human ormurine COX-I or human or murine COX-II was cloned into a BamH1 site ofthe baculovirus transfer vector pVL1393 (Invitrogen) to generate thebaculovirus transfer vectors for COX-I and COX-II in a manner similar tothe method of D. R. O'Reilly et al (Baculovirus Expression Vectors: ALaboratory Manual (1992)). Recombinant baculoviruses were isolated bytransfecting 4 μg of baculovirus transfer vector DNA into SF9 insectcells (2×10e8) along with 200 ng of linearized baculovirus plasmid DNAby the calcium phosphate method. See M. D. Summers and G. E. Smith, AManual of Methods for Baculovirus Vectors and insect Cell CultureProcedures, Texas Agric. Exp. Station Bull. 1555 (1987). Recombinantviruses were purified by three rounds of plaque purification and hightiter (10E7-10E8 pfu/ml) stocks of virus were prepared. For large scaleproduction, SF9 insect cells were infected in 10 liter fermentors(0.5×10⁶/ml) with the recombinant baculovirus stock such that themultiplicity of infection was 0.1. After 72 hours the cells werecentrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%,pH 8.0) containing 1%3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). Thehomogenate was centrifuged at 10,000×G for 3.0 minutes, and theresultant supernatant was stored at −80° C. before being assayed for COXactivity.

b. Assay for COX I and COX II Activity:

COX activity was assaved as PGE₂ formed/μg protein/time using an ELISAto detect the prostaglandin released. CHAPS-solubilized insect cellmembranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (50 mM, pH 8.0) containing epinephrine,phenol, and heme with the addition of arachidonic acid (10 μM).Compounds were pre-incubated with the enzyme for 10-20 minutes prior tothe addition of arachidonic acid. Any reaction between the arachidonicacid and the enzyme was stopped after ten minutes at 37° C./roomtemperature by transferring 40 μl of reaction mix into 160 μl ELISAbuffer and 25 μM indomethacin. The PGE₂ formed was measured by standardELISA technology (Cayman Chemical). Results are shown in Table XII.

TABLE XII Human COX II Human COX I Example ID₅₀ uM ID₅₀ uM 1 <.1 18 2<.1 15.0 3 <.1 >100 4 .6 37.5 5 <.1 6.3 6 .2 78.7 7 14 >100 8 37.7 >1009 .1 55.2 10 2.7 >100 12 20 >100 55 22 77.9 56 <.1 11.7 57 47.9 >100 58<.1 5.7 59 <.1 26.8 60 <.1 .8 82 <.1 1.1 84 <.1 65.5 85 73.6 >100 86.5 >100 96 6.5 >100 97 96 >100 98 <.1 1.7 117 .3 >100 128 1.1 >100 129<.1 13.5 130 3.6 12.5 131 .2 >100 138 .6 <.1 170 .1 >100 171 .8 >100 1724.2 >100 173 4.7 >100 174 3.5 100 175 66.9 >100 176 .3 >100 187 1.1 13.6188 .2 19.8 196 .6 4.1 197 <.1 3.4 198 4.2 56.5 199 <.1 <.1 200 <.1 .5201 <.1 2.2 202 <.1 91 203 27 >100 204 6.7 >100 205 <.1 2.1 259 1.1 >100260 1.1 >100 261 <.1 <.1 262 <.1 <.1

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. The compounds and composition may, for example, beadministered intravascularly, intraperitoneally, subcutaneously,intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compound that is administered andthe dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the disease, the route and frequency of administration, andthe particular compound employed, and thus may vary widely. Thepharmaceutical compositions may contain active ingredient in the rangeof about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mgand most preferably between about 1 and 100 mg. A daily dose of about0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50mg/kg body weight and most preferably from about 1 to 20 mg/kg bodyweight, may be appropriate. The daily dose can be administered in one tofour doses per day.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspersions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes or administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A method for the preparation of4-[5-(4-chlorophenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamidewherein the method comprises: contacting ethyl trifluoroacetate with4-chloroacetophenone in the presence of sodium methoxide and an ethersolvent to form 4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dione;and contacting the 4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dionewith 4-sulphonamidophenyl hydrazine hydrochloride in the presence ofabsolute ethyl alcohol under reflux to produce4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.